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>> WELCOME TO THE
WEDNESDAY

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AFTERNOON LECTURE SERIES, I AM

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MICHELLE ANTWON, CHIEF OF THE

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SECTION ON NEUROCIRCUITS AT NIH.

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IT IS MY GREAT PLEASURE TO

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INTRODUCE TODAY'S DISTINGUISHED

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SPEAKER DR. RICHARD TSIEN,

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DR. TSIEN DESCRIBES HIMSELF AS A

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CARDIAC AND NEURONAL

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FUNCTIONALIST AND WE ALSO SEE

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HIM AS A PIONEER IN THE VOLTAGE

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CALCIUM CHANNELS STUDIES.

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HIS INFOIVATIVE WORK DELVES INTO

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THE MECHANISMS AND ROLES OF

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THESE VESSELS IN SIN APTICAL

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FUSION, CELL SIGNALING PATHWAYS

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AND YOUR OVERARCHING IMPACT ON

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NEUROTRANSMITTER RELEASE,

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SYNAPTIC TRANSMISSION AND

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SYNAPTIC PLASTICITY IN BOTH THE

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HEALTHY AND DISEASED BRAIN.

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FOR THOSE WATCHING REMOTELY, WE

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ENCOURAGE YOU TO PARTICIPATE IN

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THE QUESTION AND ANSWER SESSION

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AFTER TODAY'S PRESENTATION.

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YOU CAN DO SO BY CLICKING ON THE

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BUTTON JUST BELOW YOUR VIDEOCAST

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WINDOW, THAT SAYS SEND LIVE

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FEEDBACK, CLICK ON THAT, TYPE

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YOUR NAME AND QUESTION AND WE

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WILL RELAY THIS MESSAGE TO

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DR. STIEN AT THE END OF HIS

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LECTURE.

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YOU CAN SUBMIT A QUESTION ANY

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TIME AND I HOPE YOU DO SO.

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FOR THOSE OF YOU IN THE

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LIPSETT AMPHITHEATRE TODAY, YOU

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CAN USE THE MICs ON THE LEFT

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AND RIGHT.

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WE ARE ALSO OFFERING CONTINUING

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MEDICAL EDUCATION CREDITS FOR

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THIS PRESENTATION, THE CME CODE

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FOR TODAY IS 50095. 

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THAT'S 50095.

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SO LET'S RESUME, OUR ESTEEMED

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SPEAKER TODAY IS DR. RICHARD

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TSIEN, WHO IS THE MILLER

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PROFESSOR OF NEUROSCIENCE OF

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CHAIR OF DEPARTMENT OF

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NEUROPHYSIOLOGY AND

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NEUROSCIENCE.

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HE EARNED HIS BACHELOR OF

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SCIENCE AND MASTER'S OF SCIENCE

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DEGREE IN ELECTRICAL ENGINEERING

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FROM THE MASSACHUSETTS INSTITUTE

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OF TECHNOLOGY.

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SUBSEQUENTLY, HE WAS AWARDED A

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ROAD SKOALARSHIP TO PURSUE HIS

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DR. OF PHILOSOPHY DEGREE, IN

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BIOPHYSICS AT THE UNIVERSITY OF

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OXFORD.

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WHERE HE CONDUCTED RESEARCH

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UNDER THE GUIDANCE OF PROFESSORS

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DENNIS NOBLE AND JULIAN JOCK,

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AFTER OXFORD DR. TSIEN JOINED

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YALE UNIVERSITY SCHOOL OF

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MEDICINE AS AN ASSISTANT

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PROFESSOR IN THE DEPARTMENT OF

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PHYSIOLOGY.

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EVENTUALLY OBTAINING THE RANK OF

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FULL PROCESSOR WITHIN 9 YEARS.

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AFTER SPENDING 18 YEARS AT YALE,

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HE RELOCATED TO STANFORD

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UNIVERSITY IN 1988 WHERE HE

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ESTABLISHED THE DEPARTMENT OF

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MOLECULAR AND CELLULAR FIELD

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FUNCTIONS YOJ AND SERVED AS ITS

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INAUGURAL CHAIRMAN, HERE HE ALSO

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SERVED AS A CO DIRECTOR FOR THE

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STANFORD BRAIN RESEARCH CENTER.

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IN 2011, DR. TSIEN LEFT STANFORD

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AS AN EMERITUS FACULTY MEMBER

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AND TRANSITIONED TO THE NEW YORK

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UNIVERSITY [INDISCERNIBLE]

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MEDICAL PROFESSOR ASSUMING THE

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POSITION OF THE NEUROLOGICAL

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DIRECTOR OF THE SCIENCE

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EN--STRATEGIESITUTE.

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IN TBENT 15 HE WAS NAMED

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INAUGURAL SCIENTIFIC DIRECTOR OF

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THE [INDISCERNIBLE] INSTITUTE

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FOR PARKINSONS AND MOVEMENT

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DISORDER AT NYU.

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DR. TSIEN HAS FEARLESSLY FORGED

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A TRAIL OF GROUPED BREAKING

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RESEARCH.

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HIS RESEARCH DOCUMENTED IN OVER

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300 PEER REVIEWED JOURNAL

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ARTICLES HAS SIGNIFICANTLY

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ADVANCED OUR UNDERSTANDING OF

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HOW NEUROTRANSMITTERS, DRUGS OF

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ABUSE AND MOLECULAR ALTERATIONS

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REGULATE CALCIUM CHANNELS.

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DR. TSIEN'S CONTRIBUTIONS EXTEND

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TO ELUCIDATING THE MECHANISMS

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THAT FACILITATE ADAPTATION OF

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SYNAPTIC STRENGTH OR ALTERATIONS

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IN NEURONAL GENE EXPRESSION,

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THROUGH CHANGES IN SYNAPTIC

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TRANSMISSION, AND

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DEPOLARIZATION, THE PRIME BRAIN

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NETWORKS FOR LEARNING AND MEMORY

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FUNCTIONS.

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ADDITIONALLY HIS WORK HAS

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YIELDED VALUABLE INSIGHTS INTO

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THE MECHIMISMS THAT,A LOW US TO

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ADAPT TO SUDDEN OR PROLONGED

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CHAIMPLES IN ACTIVITY LEVELS.

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THE IMPLICATIONS OF HIS RESEARCH

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REVERBERATE ACROSS DIVERSE

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CLINICAL DOMAINS, ENCOMPASSING

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DISEASES SUCH AS ALZHEIMER'S

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DISEASE, AUTISM, NEUROLOGICAL

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DISORDY SAYS LIKE MIGRAINE,

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ATTACKSIA, DYSTONIA, MORE OVER

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HIS FINDING ARE PERINENT TO

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TERMINAL CONDITIONS SUCH AS

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SUDDEN UNEXPECTED DEATH IN

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CHILDHOOD, DR. TSIEN IS ALL THE

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CO-AUTHOR FOR THE SEMINOLE

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TEXTBOOK, ELECTRIC CONFLUENCE IN

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EXCITABLE CELLS, A FUNDAMENTAL

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RESOURCE FOR STUDENTS STUDYING

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BIOPHYSICS, HIS LIST OF

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ACCOLADES INCLUDES THE ROLE

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SCHOLARSHIP TO THE INVESTIGATOR

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AWARD, THE KAISER AWARD, THE

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PRIZE, THE CART WRIGHT PRIZE,

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THE AXLE ROD PRICE, THE JAMILA

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ROD PRICE, THE DIRECTORSHIP,

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DISTINGUISHED JOHN BURDEN PRICE

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LECTURE OF THE UNIVERSITY OF

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OXFORD.

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NOTABLY HE HAS BEEN ELECTED AS A

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MEMBER OF THE NATIONAL ACADEMY

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OF MEDICINE, THE NATIONAL

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ACADEMY OF SCIENCES, THE

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INSTITUTE OF MEDICINE, THE

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AMERICAN ACADEMY OF ARTS AND

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SCIENCES AND THE ACADEMIA

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SENICA, WHICH IS THE NATIONAL

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ACADEMY OF THE REPUBLIC OF

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CHINA.

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THE TITLE OF DR. TSIEN'S TALK

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TODAY IS LEVERAGING GENETICS AND

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CELL SIGNALING TO DECIPHER

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DISORDERS OF EXCITABILITY.

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PLEASE WELCOME DR. TSIEN.

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[ APPLAUSE ]

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NAND AS DR. TSIEN IS APPROACHING

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THE PODIUM, WE HAD A MIX UP WITH

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THE LIVE FEEDBACK FORM, SO FOR

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THOSE WATCHING ONLINE, IF YOU

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DON'T SEE IT MAYBE IN A FEW

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MINUTES, RESILIENCE LOAD YOUR

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VIDEOCAST SYSTEM AND THE BUTTON

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WILL BE SHOWING UP IN A FEW

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MINUTES AND THE CME CODE IN CASE

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YOU MISHEARD WAS 50110.

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50110.

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THANK YOU.

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ALL YOURS DR. TSIEN.

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>> THANK YOU VERY MUCH,

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DR. ANTWON, AND THANK YOU

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DR. SHORE AND THANKS TO DIANE

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GOMEZ FOR ARRANGING THIS VISIT.

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IT'S A BIG PLEASURE FOR ME TO BE

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HERE AT NIH AND SEE FOLKS WELL

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RECOVERED FROM THE PANDEMIC AND

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I MET WONDERFUL PEOPLE TODAY,

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TRAINEES AND FACULTY AND I HOPE

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TO MEET SOME MORE DURING THE

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REST OF THE DAY.

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I WOULD LIKE TO TALK TO YOU

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ABOUT A TOPIC THAT'S VERY

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RELEVANT TO NIH AND THAT IS HOW

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WE'RE GOING TO TAKE THE

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DISCOVERIES FROM GENETICS AND

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USE THEM TO UNDERSTAND CELL

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SIGNALING AND THEREFORE TO

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DECIPHER DISORDERS OF

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EXCITABILITY, INCLUDING

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EPILEPSY, AND AUTISM AND

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EVENTUALLY SCHIZOPHRENIA.

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I HAVE NO DISCLOSURES TO MAKE

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NOR DO MEMBERS OF MY LAB, AND WE

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HAVE SUPPORT FROM A NUMBER OF

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ORGANIZATIONS MYSELFATIONS

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INCLUDING BRAIN INITIATIVE,

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NINDS, NIMH, NIDA, NIGMS, BUT

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NOT SPECIFICALLY FOR THE WORK ON

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CBD THEY WILL TELL YOU ABOUT, A

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NUMBER OF DIFFERENT FOUNDATIONS

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HAVE BEEN VERY GENEROUS TO US.

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IN TODAY'S LECTURE I WOULD LIKE

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TO SHOW OW GENETIC INSIGHTS

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PROMPT NEUROLOGICAL APPROACHES

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TO FUNCTION IN PATHOPHYSIOLOGY.

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YOU CAN READ THIS, I GUESS.

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DELINEATE WHICH EXCITATORY

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SIGNALING MOLECULES COORDINATE

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EXCITATORY AND HIPAAATORY

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FUNCTION.

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TALK A LITTLE BIT ABOUT SUDDEN

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AND UNEXPECTED DEATH IN

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CHILDHOOD AND EVENTUALLY MAKE

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PROMISSORY NOTES ABOUT HOW WE

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WILL TAKE WHAT WE KNOW ABOUT

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SIGNALING PROTEINS, AND APPLY IT

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TO A BIG DISEASE LIKE

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SCHIZOPHRENIA.

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NOW, MANY PEOPLE KNOW THAT

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NEUROLOGICAL AND PSYCHIATRIC

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DISORDERS SHARE GENES AND MAY

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EVEN SHARE THERAPEUTIC

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POTENTIAL. 

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IN THIS SLIDE FROM JOE BUXBAUM'S

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WORK, YOU CAN SEE A DIAGRAM

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SCHEMATICALLY DEPICTING HOW THE

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DIFFERENT DISEASES LIKE

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SCHIZOPHRENIA, INTELLECTUAL

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DISABILITY AND AUTISM, ACTUALLY

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OVERLAP WITH EPILEPSY IN THEIR

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GENETIC BASIS.

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MARCUS I'M HAVING TROUBLE

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FINDING THE POINTER.

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WAIT A SECOND. 

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HERE I GO.

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CAN YOU SEE THE POINTER? 

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OKAY, AND INDEED, BILL

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[INDISCERNIBLE]'S LAB CAME UP

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WITH THE IDEA THAT AS 1 EXAMPLE

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OF THIS KIND OF OVERLAP, A

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MEDICINE THAT WAS PREVIOUSLY

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USED FOR EPILEPSY OR CBD, OR

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KAN--KANA A--BITS KIOLE WAS

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EFFECTIVE IN TREATING A LEVEL OF

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AUTISM IN MOUSE LEVEL.

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THIS IS THE MOUSE NAV1.1, WHO'S

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NEURONS ARE NOT BEHAVING

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PROPERLY AND THIS EXPERIMENT BY

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NEFFA STELLA AND COLLEAGUES IT

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SHOWS IF YOU USE CBD AT

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CLINICALLY EFFECTIVE DOSES IN

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MEN, CAN YOU SEE IMPROVEMENT IN

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00:10:17,522 --> 00:10:20,158
THE SOCIAL BEHAVIOR OF A MOUSE

257
00:10:20,158 --> 00:10:23,561
BRENGS IT UP TO SORT OF CONTROL

258
00:10:23,561 --> 00:10:25,430
LEVELS AS YOU INCREASE THE DOSE.

259
00:10:25,430 --> 00:10:28,166
SO THE POSSIBILITY IS THAT AN

260
00:10:28,166 --> 00:10:29,968
ANTISEIZURE MEDICATION MIGHT

261
00:10:29,968 --> 00:10:32,704
CROSS OVER AND AFFECT A SOCIAL

262
00:10:32,704 --> 00:10:34,339
DEFICIT THAT WOULD TRADITIONALLY

263
00:10:34,339 --> 00:10:42,914
BE THE PROVINCE OF

264
00:10:42,914 --> 00:10:43,248
PSYCHIATRISTS.

265
00:10:43,248 --> 00:10:45,016
NOW I WOULD LIKE TO TALK ABOUT

266
00:10:45,016 --> 00:10:49,587
CBD BECAUSE IT RINGS BELLS WITH

267
00:10:49,587 --> 00:10:51,222
ENDOKACCT NABBOIDS AND IT IS A

268
00:10:51,222 --> 00:10:52,724
MEDICINE THAT'S BEEN FDA

269
00:10:52,724 --> 00:10:52,991
APPROVED.

270
00:10:52,991 --> 00:10:56,661
ON 1 HAND WE HAVE THE CONTRAST

271
00:10:56,661 --> 00:10:59,364
BETWEEN THE PSYCHOACTIVE

272
00:10:59,364 --> 00:11:03,835
INGREDIENT OF CANNABIS, KELTA 9

273
00:11:03,835 --> 00:11:08,573
THH AND KAN--KANAA BIN OIL, THE

274
00:11:08,573 --> 00:11:09,173
NONPSYCHOTROAPIC, AND THAT'S

275
00:11:09,173 --> 00:11:11,476
IMPORTANT THING FOR ITS USE AS A

276
00:11:11,476 --> 00:11:11,743
MEDICINE.

277
00:11:11,743 --> 00:11:15,013
THC AS A NUMBER OF PEOPLE ARE

278
00:11:15,013 --> 00:11:17,148
STUDYING, CAN HAVE A NUMBER OF

279
00:11:17,148 --> 00:11:21,352
DIFFERENT EFFECTS, INCLUDING

280
00:11:21,352 --> 00:11:25,456
INCREASING HUNGER WHEREAS ON THE

281
00:11:25,456 --> 00:11:27,625
OTHER HAND CANNABITIOL CAN

282
00:11:27,625 --> 00:11:28,927
COUNTERACT THESE SIDE EFFECTS OF

283
00:11:28,927 --> 00:11:31,596
DELTA 9 AND FINALLY THE CB1

284
00:11:31,596 --> 00:11:33,431
RECEPTOR IS THE TARGET OF

285
00:11:33,431 --> 00:11:35,934
INVESTIGATION OF MANY PEOPLE AT

286
00:11:35,934 --> 00:11:39,504
NIH INCLUDING GEORGE KUNOS, BUT

287
00:11:39,504 --> 00:11:42,040
THE CBD HAS VERY LOW AFFINITY AT

288
00:11:42,040 --> 00:11:42,941
THE CB1 RECEPTOR.

289
00:11:42,941 --> 00:11:44,008
SO THESE CHEMICALS ARE VERY

290
00:11:44,008 --> 00:11:47,245
CLOSE TO EACH OTHER, THE KEY

291
00:11:47,245 --> 00:11:55,453
DIFFERENCE LIES IN THIS OXYGEN

292
00:11:55,453 --> 00:11:58,222
SPANNING LINK BETWEEN THESE 2

293
00:11:58,222 --> 00:11:59,691
WHICH EXISTS IN CBD.

294
00:11:59,691 --> 00:12:01,626
NOW THE MEDICAL MOTIVATIONS ARE

295
00:12:01,626 --> 00:12:02,594
ABUBD ANT.

296
00:12:02,594 --> 00:12:05,063
FDA AS PROVED FOLLOWING A SERIES

297
00:12:05,063 --> 00:12:05,930
OF DOUBLE BRINEDDED CLINICAL

298
00:12:05,930 --> 00:12:13,004
STUDIES FOR ITS USE IN THE

299
00:12:13,004 --> 00:12:14,172
TREATMENT OF DRAVET SYNDROME

300
00:12:14,172 --> 00:12:17,475
WHICH IS A FORM OF INTRACTABLE

301
00:12:17,475 --> 00:12:20,612
EPILEPSY AND CBD CAUSED A 40%

302
00:12:20,612 --> 00:12:23,514
REDUCTION IN SEIZURE FREQUENCY,

303
00:12:23,514 --> 00:12:25,917
LIKEWISE IN LENOIR OX

304
00:12:25,917 --> 00:12:26,718
[INDISCERNIBLE] SYNDROME, A

305
00:12:26,718 --> 00:12:29,854
ANOTHER FORM OF EPILEPSY, A

306
00:12:29,854 --> 00:12:30,355
SIMILAR MODIFICATION WAS

307
00:12:30,355 --> 00:12:30,622
CHAIMPLED.

308
00:12:30,622 --> 00:12:32,357
SO IT'S ALREADY BEEN APPROVED

309
00:12:32,357 --> 00:12:34,425
AND ON THE STREET MANY PEOPLE

310
00:12:34,425 --> 00:12:37,161
ARE USING IT FOR ANYTHING FROM

311
00:12:37,161 --> 00:12:39,030
ANXIETY TO INSOMNIA AND NOT

312
00:12:39,030 --> 00:12:40,665
WORRYING ABOUT WHAT DOSE THEY'RE

313
00:12:40,665 --> 00:12:42,567
USING OR HOW GOOD THE DRUG THERE

314
00:12:42,567 --> 00:12:43,835
IS, SO THERE'S ACTUALLY AN

315
00:12:43,835 --> 00:12:46,904
EXPERIMENT GOING ON AS WE OUT ON

316
00:12:46,904 --> 00:12:48,406
THE STREET OF PEOPLE

317
00:12:48,406 --> 00:12:49,140
EXPERIMENTING WITH THIS AGENT

318
00:12:49,140 --> 00:12:50,908
AND BECAUSE IT DOESN'T PRODUCE A

319
00:12:50,908 --> 00:12:52,977
HIGH AND IS NOT ILLEGAL, THERE'S

320
00:12:52,977 --> 00:12:57,849
A LOT OF TESTING GOING ON.

321
00:12:57,849 --> 00:12:59,784
THE QUESTION IS, HOW DOES IT

322
00:12:59,784 --> 00:13:01,419
ACTUALLY WORK AND IF WE LEARN

323
00:13:01,419 --> 00:13:05,523
HOW IT REALLY WORKS CAN WE APPLY

324
00:13:05,523 --> 00:13:07,592
IT MORE INTELLIGENTLY AND

325
00:13:07,592 --> 00:13:08,559
TARGETED WAY TO AFFECT DISEASE

326
00:13:08,559 --> 00:13:09,327
OF THE BRAIN.

327
00:13:09,327 --> 00:13:11,429
THIS IS WORK DONE BY WHAT I

328
00:13:11,429 --> 00:13:15,700
MIGHT CALL THE CBD TEAM HEADED

329
00:13:15,700 --> 00:13:18,670
BY EVAN ROSENBERG, AN MD-Ph.D.

330
00:13:18,670 --> 00:13:20,772
STUDENT DOING CLINICAL TRAINING

331
00:13:20,772 --> 00:13:25,243
AT PENN, AND SIMON CHAMBER LAND,

332
00:13:25,243 --> 00:13:25,743
AN ELECTROPHYSIOLOGIST

333
00:13:25,743 --> 00:13:29,013
EXTRAORDINARY ALONG WITH ERICA

334
00:13:29,013 --> 00:13:32,583
NEBET, WHOSE GONE ON TO MEDICAL

335
00:13:32,583 --> 00:13:38,489
SCHOOL, ALEJANDRO SALAH, AND

336
00:13:38,489 --> 00:13:39,190
GOUOLIING TIAN AND XIAOHAN WANG,

337
00:13:39,190 --> 00:13:44,095
AND I WILL TALK ABOUT THEM SOON.

338
00:13:44,095 --> 00:13:47,632
WE WERE JOINED BY HELEN SHARP

339
00:13:47,632 --> 00:13:49,767
MAN, [INDISCERNIBLE] JANE AND

340
00:13:49,767 --> 00:13:50,702
YURI, [INDISCERNIBLE], AND DREW

341
00:13:50,702 --> 00:13:52,103
JONES AND REBECCA ROSE AND WE

342
00:13:52,103 --> 00:13:54,072
TEAMED UP WITH A GROUP AT THE

343
00:13:54,072 --> 00:13:55,473
UNIVERSITY OF REDDING WHOSE WORK

344
00:13:55,473 --> 00:13:57,875
I WILL SHOUT OUT ABOUT ALONG

345
00:13:57,875 --> 00:14:02,146
WITH OTHER PEOPLE IN THE UK

346
00:14:02,146 --> 00:14:03,347
TOGETHER WITH GW

347
00:14:03,347 --> 00:14:03,715
PHARMACEUTICALS.

348
00:14:03,715 --> 00:14:06,417
SIMON IS GOING ON TO A FACULTY

349
00:14:06,417 --> 00:14:07,452
JOB AT THE UNIVERSITY OF

350
00:14:07,452 --> 00:14:07,752
PITTSBURGH.

351
00:14:07,752 --> 00:14:09,654
NOW THERE ARE MULTIPLE

352
00:14:09,654 --> 00:14:15,393
CANDIDATES FOR CBD ACTION EMPLOY

353
00:14:15,393 --> 00:14:18,062
INCLUDING THE CB1 RECEPTOR, OR

354
00:14:18,062 --> 00:14:21,933
ENZYMES THAT ARE INVOLVED IN THE

355
00:14:21,933 --> 00:14:23,201
PROSECTION OF AEA, IT CAN ALSO

356
00:14:23,201 --> 00:14:25,503
HAVE ACTIONS ON OTHER LIGANDATED

357
00:14:25,503 --> 00:14:28,940
TRANLES, TRIP KAN--KANA CHEALS,

358
00:14:28,940 --> 00:14:30,374
THELP TRIP CALCIUM CHANNELS BUT

359
00:14:30,374 --> 00:14:32,577
TODAY WE WILL FOCUS ON ITS

360
00:14:32,577 --> 00:14:36,447
ACTION IN 1 PARTICULAR TARGET IN

361
00:14:36,447 --> 00:14:40,051
ORPHAN G-PROTEIN RECEPTOR CALLED

362
00:14:40,051 --> 00:14:40,318
GPR55.

363
00:14:40,318 --> 00:14:42,620
THIS MOLECULE LIVES IN THE

364
00:14:42,620 --> 00:14:44,989
MEMBRANE AND RESPONDS TO

365
00:14:44,989 --> 00:14:47,925
STIMULATION BY ITS ENDOGENOUS

366
00:14:47,925 --> 00:14:52,897
LIAISON IMAND, CALLED LPI, THAT

367
00:14:52,897 --> 00:14:56,868
AGANISM IS BLOCKED BY CBD AS A

368
00:14:56,868 --> 00:14:58,169
COMPETITIVE ANTAGONIST.

369
00:14:58,169 --> 00:15:00,505
SO THIS COMBINATION OF A NATURAL

370
00:15:00,505 --> 00:15:01,906
LIGAND, RECEPTOR AND ANTAGONIST,

371
00:15:01,906 --> 00:15:03,374
IS THE BASIS FOR THIS STORY,IME

372
00:15:03,374 --> 00:15:05,076
GOING TO TELL YOU IN THE FIRST

373
00:15:05,076 --> 00:15:07,979
PART OF MY TALK.

374
00:15:07,979 --> 00:15:10,648
WHY ARE WE INTERESTED IN THESE

375
00:15:10,648 --> 00:15:11,516
AGENTS?

376
00:15:11,516 --> 00:15:13,451
BECAUSE OF GENETICS.

377
00:15:13,451 --> 00:15:16,387
GENETICS TELLS US FIRST OF ALL

378
00:15:16,387 --> 00:15:19,624
THAT LPA IS INTERESTING, THAT'S

379
00:15:19,624 --> 00:15:20,324
BECAUSEIOSEVERE MITRAL GLEASON

380
00:15:20,324 --> 00:15:22,794
TEAMED UP WITH GROUPS IN

381
00:15:22,794 --> 00:15:25,329
PAKISTAN AND OTHER COUNTRIES IN

382
00:15:25,329 --> 00:15:30,001
ASIA AND STUDIED THE METABOLISM

383
00:15:30,001 --> 00:15:30,935
OF LPI.

384
00:15:30,935 --> 00:15:34,205
LPI IS PRODUCED AS A PRODUCT OF

385
00:15:34,205 --> 00:15:38,910
FOSTER NURSED FOCUSED ON TITLE

386
00:15:38,910 --> 00:15:40,678
INOCITOLL, A LIPID PRESENT IN

387
00:15:40,678 --> 00:15:46,284
ALL MEMBRANES AND VERY IMPORTANT

388
00:15:46,284 --> 00:15:47,952
AS A REPOSITORY FOR

389
00:15:47,952 --> 00:15:48,820
[INDISCERNIBLE] ACID.

390
00:15:48,820 --> 00:15:52,123
WHEN CLEAVAGE IS DONE FOR FOSTER

391
00:15:52,123 --> 00:15:54,625
NURSED POETIC LIPASE 2, THE

392
00:15:54,625 --> 00:15:56,460
MODEL CITIZENETY IS CLIPPED OFF

393
00:15:56,460 --> 00:16:04,936
LEAVING YOU WITH AN ACEL CARBON

394
00:16:04,936 --> 00:16:08,573
CHAIN LEADING TO LPI, AND THE

395
00:16:08,573 --> 00:16:10,908
SIN KRETTIC ENZYME FOR THIS IS

396
00:16:10,908 --> 00:16:11,576
CALCIUM DEPEND EPT.

397
00:16:11,576 --> 00:16:13,611
SO AS A RESULT OF ELECTRICAL

398
00:16:13,611 --> 00:16:14,612
ACTIVITY IN NEURONS, THERE IS

399
00:16:14,612 --> 00:16:17,515
MODEL CITIZEN DUKS OF LPI.

400
00:16:17,515 --> 00:16:21,686
THE REVERSE ENZYME CALLED

401
00:16:21,686 --> 00:16:22,687
LPUNISHING I ACE ILLEGALS

402
00:16:22,687 --> 00:16:26,057
TRANSFER ACE, AND IT'S THE ONLY

403
00:16:26,057 --> 00:16:27,825
ENZYME KNOWN TO CONVERT LPI FROM

404
00:16:27,825 --> 00:16:32,163
THIS ACTIVE FORM BACK BO THE PI

405
00:16:32,163 --> 00:16:32,597
RESERVOIR.

406
00:16:32,597 --> 00:16:34,932
WHEN YOU HAVE MUTATIONS IN THIS

407
00:16:34,932 --> 00:16:38,669
ENZYME, AND THAT WAS STUDIED IN

408
00:16:38,669 --> 00:16:41,873
HIGHLY INBRED FAMILIES IN

409
00:16:41,873 --> 00:16:42,907
VARIOUS COUNTRIES, COUSINS

410
00:16:42,907 --> 00:16:45,109
MARRYING EACH OTHER JUST LIKE IN

411
00:16:45,109 --> 00:16:49,547
THE ROYALTY OF THE EUROPEAN

412
00:16:49,547 --> 00:16:51,282
CAPITALS, THE RESULT IS

413
00:16:51,282 --> 00:16:52,216
ENACTIVATING MUTATIONS THAT ARE

414
00:16:52,216 --> 00:16:55,419
DOUBLED UP ON BOTH ALLELES AND

415
00:16:55,419 --> 00:16:58,489
THEREFORE, CAUSE EPILEPSY,

416
00:16:58,489 --> 00:16:59,223
AUTISM, AND INCOLLECTUAL

417
00:16:59,223 --> 00:17:03,127
DISABILITY, SO THERE WAS GENETIC

418
00:17:03,127 --> 00:17:08,099
EVIDENCE THAT THE ABSENCE OF

419
00:17:08,099 --> 00:17:10,568
BREAK DOWN OR DISPOSAL OF LPI

420
00:17:10,568 --> 00:17:11,469
COULD CAUSE DISEASE, HOWEVER,

421
00:17:11,469 --> 00:17:14,005
THE PEOPLE WHO DID THE STUDY

422
00:17:14,005 --> 00:17:16,107
INTERPRETED, NOT IN TERMS OF THE

423
00:17:16,107 --> 00:17:18,609
BAD THINGS THAT TOO MUCH LPI

424
00:17:18,609 --> 00:17:21,345
WOULD DO, BUT RATHER THE BAD

425
00:17:21,345 --> 00:17:23,180
THINGS THAT MIGHT HAPPEN IF YOU

426
00:17:23,180 --> 00:17:24,615
HAD TOO LITTLE PI, AND WE'RE

427
00:17:24,615 --> 00:17:27,385
GOING TO MAKE THE CASE THAT IT'S

428
00:17:27,385 --> 00:17:30,121
ACTUALLY LPI THAT IS THE BAD

429
00:17:30,121 --> 00:17:36,928
ACTOR AND THAT LPI ITS KNOWN

430
00:17:36,928 --> 00:17:39,096
RECEPTOR GPR55 AND THAT EFFECT

431
00:17:39,096 --> 00:17:41,332
IS ANTAGONIZED BY CBD, SO

432
00:17:41,332 --> 00:17:45,937
GENETICS LEADS US TO THE LIGAND

433
00:17:45,937 --> 00:17:48,072
AND ASSOCIATION THROUGH WORK OF

434
00:17:48,072 --> 00:17:51,976
OTHER PEOPLE TELLS US ABOUT GPR

435
00:17:51,976 --> 00:17:54,045
55 AND C BD.

436
00:17:54,045 --> 00:17:57,715
SO IF YOU USE A KNOCK OUT MOUSE,

437
00:17:57,715 --> 00:17:59,917
KINDLY PROVIDED TO US BY KENNETH

438
00:17:59,917 --> 00:18:03,988
MACKEY OF INDIANA UNIVERSITY,

439
00:18:03,988 --> 00:18:06,190
YOU CAN SEE THAT GPR 55 IS

440
00:18:06,190 --> 00:18:08,392
ABSENT IN A REGION OF BRAIN,

441
00:18:08,392 --> 00:18:09,460
IMPORTANT FOR EPILEPSY AND

442
00:18:09,460 --> 00:18:11,796
LEARNING AND MEMORY CALLED A

443
00:18:11,796 --> 00:18:12,330
HIPPOCAMPUS.

444
00:18:12,330 --> 00:18:15,132
SO HERE WE HAVE STAINING FOR GPR

445
00:18:15,132 --> 00:18:17,234
55, HERE WE HAVE ONLY STAINING

446
00:18:17,234 --> 00:18:20,004
FOR THE NUCLEUS OF THE CELL AND

447
00:18:20,004 --> 00:18:24,842
NO GPR 55 AND IF YOU TAKE MICE,

448
00:18:24,842 --> 00:18:27,111
AND TREAT THEM WITH PENTINE

449
00:18:27,111 --> 00:18:29,046
REGIMEN O LEAN [INDISCERNIBLE]

450
00:18:29,046 --> 00:18:31,148
TO INDUCE SEIZURES, YOU FIND

451
00:18:31,148 --> 00:18:33,117
THERE'S A DOSE REDUNDANT

452
00:18:33,117 --> 00:18:35,353
INDUCTION IN SEIZURES IN

453
00:18:35,353 --> 00:18:37,488
RESPONSE TO INCREASING AMOUNTS

454
00:18:37,488 --> 00:18:39,223
OF CBD BUT THAT DOZE DEPENDENCE

455
00:18:39,223 --> 00:18:42,693
IS GONE IN THE GPR55 KNOCK OUT

456
00:18:42,693 --> 00:18:43,694
EMPLOY SUGGIEST THAGOREAN GPR55

457
00:18:43,694 --> 00:18:49,600
MIGHT HAVE SOMETHING TO DO WITH

458
00:18:49,600 --> 00:18:50,368
THE SEIZURES.

459
00:18:50,368 --> 00:18:52,003
WHAT HAPPENS TO NEURONAL

460
00:18:52,003 --> 00:18:52,970
FUNCTION?

461
00:18:52,970 --> 00:18:54,772
WE STUDIED THAT IN SLICES FROM

462
00:18:54,772 --> 00:18:59,343
THE HIPPOCAMPUS THAT HAVE THE

463
00:18:59,343 --> 00:19:02,413
CLASSICAL REGIONS SCRIBED BY

464
00:19:02,413 --> 00:19:03,114
RAMONEIC [INDISCERNIBLE] ET ALL,

465
00:19:03,114 --> 00:19:05,249
WHICH IS THE TARGET OF SYNAPSES

466
00:19:05,249 --> 00:19:08,319
GIVEN OFF BY CA3 PARAMETAL ISS

467
00:19:08,319 --> 00:19:11,188
THAT SEND AXONS ALONG THE

468
00:19:11,188 --> 00:19:12,723
SHAFTER COLLATERALS TO

469
00:19:12,723 --> 00:19:14,992
INNERIVATE THE CAC1 NEURONS AND

470
00:19:14,992 --> 00:19:16,994
WHEN WE STIMULATE THOSE AXONS

471
00:19:16,994 --> 00:19:19,063
WITH AN EXTRA CELLULAR STIMULUS,

472
00:19:19,063 --> 00:19:22,933
WE FIND THAT THE STIMULUS IS

473
00:19:22,933 --> 00:19:24,535
FOLLOWED BOY ACTION POTENTIALS

474
00:19:24,535 --> 00:19:26,437
THAT RECORDED AS EXTRA CELLULAR

475
00:19:26,437 --> 00:19:30,408
CURRENTS SHOWN HERE AND THAT LPI

476
00:19:30,408 --> 00:19:32,476
INCREASES THE INCIDENCE OF

477
00:19:32,476 --> 00:19:36,514
SUCCESSFUL FIRING BY ABOUT 50%

478
00:19:36,514 --> 00:19:39,016
AND AN EFFECT THAT DISAPPEARS IF

479
00:19:39,016 --> 00:19:43,554
YOU MAINTAIN EXPOSEDDURE TO LPI.

480
00:19:43,554 --> 00:19:45,623
SO WE CAN THEN LOOK AT THE

481
00:19:45,623 --> 00:19:47,591
EFFECT OF CBD AND SHOW THAT THE

482
00:19:47,591 --> 00:19:49,326
EFFECT OF THE KNOCK OUT IS

483
00:19:49,326 --> 00:19:51,529
MIMICKED BY THE EFFECTIVE CBD.

484
00:19:51,529 --> 00:19:55,032
SO THIS IS EXACTLY WHAT YOU

485
00:19:55,032 --> 00:19:59,036
WOULD EXPECT IF A RECEPTOR,

486
00:19:59,036 --> 00:20:01,038
G-PROTEIN RECEPTOR AND CBD WAS

487
00:20:01,038 --> 00:20:03,140
THE ANTAGONIST FOR IT SO WHEN

488
00:20:03,140 --> 00:20:06,077
YOU HAVE CBD PRESENT, IT'S AS IF

489
00:20:06,077 --> 00:20:08,746
THERE WAS SO RECEPTOR AT ALL AND

490
00:20:08,746 --> 00:20:10,948
LPI WAS THE ENDOGENOUS LIGAND

491
00:20:10,948 --> 00:20:13,150
THAT INCREASE THE RATE OF ACTION

492
00:20:13,150 --> 00:20:14,485
POTENTIALS BY ABOUT 50%.

493
00:20:14,485 --> 00:20:17,321
THIS IS HARDLY EPILEPSY BUT IT'S

494
00:20:17,321 --> 00:20:18,422
DONE UNDER MILD CONDITIONS WHERE

495
00:20:18,422 --> 00:20:20,391
WE'RE LOOKING TO SEE THAT

496
00:20:20,391 --> 00:20:22,960
THERE'S A PHYSIOLOGICAL EFFECT.

497
00:20:22,960 --> 00:20:25,930
NOW TO UNDERSTAND HOW CBD HAD

498
00:20:25,930 --> 00:20:29,533
THIS ACTION ON TRANSMISSION,

499
00:20:29,533 --> 00:20:31,902
FROM THE SHAFT COLLATERALS TO

500
00:20:31,902 --> 00:20:36,607
THE CAC1 NEURONS, WE RECORD

501
00:20:36,607 --> 00:20:38,476
QUANTAL SYNAPTIC EEIVETS FROM

502
00:20:38,476 --> 00:20:42,813
THE CAC1 NEURONS THESE ARE CALL

503
00:20:42,813 --> 00:20:51,789
MINIATURES OR MEPSCs, THIS IS

504
00:20:51,789 --> 00:20:54,425
TRIGGERED BY GLUTEA MITTURGIC

505
00:20:54,425 --> 00:20:54,758
TRANSMISSION.

506
00:20:54,758 --> 00:20:57,261
AND IF WE SHRINK THESE DOWN AND

507
00:20:57,261 --> 00:20:59,130
CHANGE THE TIME SCALE TO RECORD

508
00:20:59,130 --> 00:21:01,832
OVER A MINUTE RATHER THAN 2

509
00:21:01,832 --> 00:21:03,200
MILLI SECONDS, WE SEE

510
00:21:03,200 --> 00:21:05,269
SPONTANEOUS RELEASE OF QUAWPT

511
00:21:05,269 --> 00:21:06,203
UMKC FROM THE PRESYNAPTIC

512
00:21:06,203 --> 00:21:08,139
TERMINALS AND THAT LPI GREATLY

513
00:21:08,139 --> 00:21:10,508
INCREASES THE FREQUENCY OF THESE

514
00:21:10,508 --> 00:21:12,143
QUANTA AND THE EFFECT OF THIS IS

515
00:21:12,143 --> 00:21:14,545
REVERSIBLE AND THIS IS THE TIME

516
00:21:14,545 --> 00:21:17,748
PLOT SHOWING THAT ON AVERAGE,

517
00:21:17,748 --> 00:21:19,750
THERE'S SOMETHING LIKE A 70%

518
00:21:19,750 --> 00:21:23,120
INCREASE IN FREQUENCY WHICH IS

519
00:21:23,120 --> 00:21:24,655
TRANSIENT, AND NO CHANGE IN THE

520
00:21:24,655 --> 00:21:27,424
AMPLITUDE OF THE SYNAPTIC

521
00:21:27,424 --> 00:21:27,992
EVENTS.

522
00:21:27,992 --> 00:21:30,161
EVIDENTLY THE PRESYNAPTIC

523
00:21:30,161 --> 00:21:31,462
TERMINAL IS RELEASING MORE

524
00:21:31,462 --> 00:21:32,530
QUANTUM PER UNIT PERIOD OF TIME

525
00:21:32,530 --> 00:21:35,566
AND THIS LEADS TO A TRANSIENT

526
00:21:35,566 --> 00:21:39,270
INCREASE IN EXCITATORY

527
00:21:39,270 --> 00:21:39,603
TRANSMISSION.

528
00:21:39,603 --> 00:21:41,705
THIS IS COMPLETELY BLOCKED BY

529
00:21:41,705 --> 00:21:46,410
CBD, SO FITTING WITH THE IDEA

530
00:21:46,410 --> 00:21:48,512
THAT IT'S PLOKING THE RECEPTOR

531
00:21:48,512 --> 00:21:52,049
FOR THESE DOWN STREAM EVENTS

532
00:21:52,049 --> 00:21:52,783
PRESUMABLYOT PRESYNAPTIC

533
00:21:52,783 --> 00:21:53,050
TERMINAL.

534
00:21:53,050 --> 00:21:57,955
PREVIOUS WORK ON THIS BY DIMITRI

535
00:21:57,955 --> 00:21:58,989
[INDISCERNIBLE]'S LAB WAS

536
00:21:58,989 --> 00:22:02,393
CONFIRMED BY THIS SLIDE, THIS

537
00:22:02,393 --> 00:22:02,793
FIGURE.

538
00:22:02,793 --> 00:22:06,163
WE WENT ON TO LOCK AT CHANGES IN

539
00:22:06,163 --> 00:22:06,830
THE INHIBITORY TRANSMISSION,

540
00:22:06,830 --> 00:22:08,866
AFTERALL THIS IS ONLY A

541
00:22:08,866 --> 00:22:09,633
TRANSIENT CHANGE.

542
00:22:09,633 --> 00:22:11,969
PERHAPS THERE WAS A CHANGE IN

543
00:22:11,969 --> 00:22:13,337
INHIBITORY TRANSMISSION THAT WAS

544
00:22:13,337 --> 00:22:16,640
MORE SUSTAINED, SO WE RECORDED

545
00:22:16,640 --> 00:22:19,109
INHIBITORY EVENTS LIKE THIS,

546
00:22:19,109 --> 00:22:25,749
ONLY NOT CARRIED BY SODIUM IONS

547
00:22:25,749 --> 00:22:28,152
BUT CARRIED BY CHLORON IONS AND

548
00:22:28,152 --> 00:22:30,588
WE FOUND IN THIS CASE, THE

549
00:22:30,588 --> 00:22:32,323
FREQUENCY OF EVENTS WAS NOT VERY

550
00:22:32,323 --> 00:22:33,157
MUCH CHANGED.

551
00:22:33,157 --> 00:22:34,925
WHAT WAS MAINLY CHANGED WAS THE

552
00:22:34,925 --> 00:22:36,327
AMPLITUDE OF THE EVENTS, YOU CAN

553
00:22:36,327 --> 00:22:37,861
SEE ALL THESE EVENTS ARE SMALLER

554
00:22:37,861 --> 00:22:42,399
AND THAT SHOWN HERE ON A SLOWER

555
00:22:42,399 --> 00:22:44,868
TIME SCALE OVER 10-20 MINUTES,

556
00:22:44,868 --> 00:22:47,705
THERE'S PROGRESSIVE DEVELOPMENT

557
00:22:47,705 --> 00:22:49,139
IN THE EFFECT.

558
00:22:49,139 --> 00:22:51,108
THERE'S A SLIGHT DECREASE IN

559
00:22:51,108 --> 00:22:53,377
FREQUENCY AND THERE'S A VERY

560
00:22:53,377 --> 00:22:55,479
CLEAR DECREASE IN AMPLITUDE OF

561
00:22:55,479 --> 00:22:59,049
THE SYNAPTIC EEIVETS AND THIS IS

562
00:22:59,049 --> 00:23:00,985
ALSO BLOCKED BY LPI, SO

563
00:23:00,985 --> 00:23:03,821
EVIDENTLY THE RECEPTOR IS

564
00:23:03,821 --> 00:23:06,523
COUPLED TO CHANGES BOTH IN

565
00:23:06,523 --> 00:23:07,291
EXCITATORY AND INHIBITORY

566
00:23:07,291 --> 00:23:08,892
TRANSMISSION, AND IN SLIDES I

567
00:23:08,892 --> 00:23:10,060
DECIDED TO LEAVE OUT, BECAUSE

568
00:23:10,060 --> 00:23:13,564
IT'S IN OUR PAPER, AND TAKES

569
00:23:13,564 --> 00:23:15,432
ABOUT 5 MINUTES TO EXPLAIN, WE

570
00:23:15,432 --> 00:23:16,867
WORKED OUT THE MECHANISM OF

571
00:23:16,867 --> 00:23:19,837
THIS, WE FOUND THAT THE NUMBER

572
00:23:19,837 --> 00:23:21,905
OF GABBA RECEPTORS IN THE POST

573
00:23:21,905 --> 00:23:24,308
SYNAPTIC CELL, IN THE CAC1

574
00:23:24,308 --> 00:23:29,947
PARAMETAL IS WAS DECREASED AND

575
00:23:29,947 --> 00:23:33,517
THAT THIS INVOLVED A PERFECTLY

576
00:23:33,517 --> 00:23:36,887
CONVENTIONAL MODULATION OF

577
00:23:36,887 --> 00:23:38,522
INHIBITORY TRANSMISSION.

578
00:23:38,522 --> 00:23:41,692
SO EVAN THEN WENT ON TO STUDY

579
00:23:41,692 --> 00:23:43,627
EVOKE STIMULATION BY STUDYING

580
00:23:43,627 --> 00:23:46,230
THE SAME INPUT THAT LED TO THE

581
00:23:46,230 --> 00:23:47,598
EVOKED ACTION POTENTIALS,

582
00:23:47,598 --> 00:23:48,832
RECORDING FROM THE PARAMETRAL

583
00:23:48,832 --> 00:23:56,206
NEURON BUT NOW IN RESPONSE TO AN

584
00:23:56,206 --> 00:24:01,445
ELECTRICAL INPUT AND THIS SHOWED

585
00:24:01,445 --> 00:24:03,480
RESULTS COMPATIBLE WITH THESE,

586
00:24:03,480 --> 00:24:04,915
AND THAT PRIMARILY THAT WAS

587
00:24:04,915 --> 00:24:07,751
CAUSED AN INCREASE IN THE

588
00:24:07,751 --> 00:24:13,057
EVOCKED TRANSMISSION, AND IT WAS

589
00:24:13,057 --> 00:24:14,358
MIMIC THE GPR55 RECEPTOR THERE

590
00:24:14,358 --> 00:24:16,427
WERE ALSO CHANGES IN PAIR POST

591
00:24:16,427 --> 00:24:18,629
MODULATION, WHICH ARE HERE FOR

592
00:24:18,629 --> 00:24:20,364
THE OFFICKIAN ADOS WHO ARE

593
00:24:20,364 --> 00:24:21,665
INTERESTED IN FIGURING OUT

594
00:24:21,665 --> 00:24:23,534
WHETHER THIS IS PREOR POST

595
00:24:23,534 --> 00:24:26,403
SYNAPTIC, NOT ONLY DID WE SEE

596
00:24:26,403 --> 00:24:26,970
CHANGES IN EXCITATORY

597
00:24:26,970 --> 00:24:28,806
TRANSMISSION BUT WE'RE PLEASED

598
00:24:28,806 --> 00:24:30,507
TO SEE A CHANGE IN THE

599
00:24:30,507 --> 00:24:33,510
INHIBITION WHICH IS PRODUCED

600
00:24:33,510 --> 00:24:37,247
WHEN THE COLLATERAL GIVE OFF

601
00:24:37,247 --> 00:24:40,117
BRANCHES IN INNERIVATE

602
00:24:40,117 --> 00:24:41,385
INHIBITORY NEURONS THAT INTURN

603
00:24:41,385 --> 00:24:44,021
SYNAPSE ON TO THE PARAMETAL ISS,

604
00:24:44,021 --> 00:24:46,390
THIS IS CALLED DISCIPLINARY

605
00:24:46,390 --> 00:24:48,192
SYNAPTIC INHIBITION, AND WE SAW

606
00:24:48,192 --> 00:24:50,728
A BIG DECREASE IN THE SIGNIFY

607
00:24:50,728 --> 00:24:52,196
SYNAPTIC INHIBITION IN RESPONSE

608
00:24:52,196 --> 00:24:53,897
TO CBD, SO THIS IS THE DECREASE,

609
00:24:53,897 --> 00:24:56,867
IT'S SOMETHING LIKE A 60 OR 70%

610
00:24:56,867 --> 00:24:57,134
DECREASE.

611
00:24:57,134 --> 00:24:59,737
AND ONCE AGAIN, THIS IS

612
00:24:59,737 --> 00:25:02,573
PREVENTED BY BLOCKING THE

613
00:25:02,573 --> 00:25:04,007
RECEPTORS WITH CBD, IT'S

614
00:25:04,007 --> 00:25:05,209
MIMICKED BY KNOCKING OUT THE

615
00:25:05,209 --> 00:25:08,145
RECEPTOR AND THE CHANGES WE SEE

616
00:25:08,145 --> 00:25:11,448
IN AMPLITUDE ARE PARALLEL BY

617
00:25:11,448 --> 00:25:13,817
CHANGES IN PAIRED PULSE

618
00:25:13,817 --> 00:25:15,686
MODULATION, THERE IS A BIG

619
00:25:15,686 --> 00:25:18,322
INCREASE IN HOW MUCH BIGGER THE

620
00:25:18,322 --> 00:25:21,492
SECOND RESPONSE IS TO THE FIRST,

621
00:25:21,492 --> 00:25:23,227
INDICATING A RECOVERY OF RELEASE

622
00:25:23,227 --> 00:25:24,862
PROBABILITY AND THAT ONCE AGAIN

623
00:25:24,862 --> 00:25:26,864
IS BLOCKED BY CBD AND MIMICKED

624
00:25:26,864 --> 00:25:29,266
BY THE KNOCK OUT.

625
00:25:29,266 --> 00:25:30,067
SO EVIDENTLY, RELEASE

626
00:25:30,067 --> 00:25:33,404
PROBABILITY IS GOING WAY DOWN IN

627
00:25:33,404 --> 00:25:43,013
RESPONSE TO LPI.

628
00:25:43,013 --> 00:25:44,415
O WE WENT THROUGH THIS, I WON'T

629
00:25:44,415 --> 00:25:49,052
TAKE YOU THROUGH IT, IT'S

630
00:25:49,052 --> 00:25:50,654
SHOWING THAT THE INTENSITY IN

631
00:25:50,654 --> 00:25:54,224
CLUSTERS HAS GONE DOWN AND

632
00:25:54,224 --> 00:25:56,427
THAT'S BECAUSE GEFFERIN HAS GONE

633
00:25:56,427 --> 00:25:59,263
DOWN, AND THE GABBA 2 HAS GONE

634
00:25:59,263 --> 00:26:01,932
DOWN I WILL SKIP THAT TO SAVE

635
00:26:01,932 --> 00:26:02,132
TIME.

636
00:26:02,132 --> 00:26:04,435
NOW THE KEY QUESTION IS HOW DOES

637
00:26:04,435 --> 00:26:05,969
THIS PHENOMENA RELATE TO

638
00:26:05,969 --> 00:26:09,206
EPILEPSY, IS THERE SOMETHING

639
00:26:09,206 --> 00:26:11,575
AUTOCATALYTIC OR REGENERATIVE

640
00:26:11,575 --> 00:26:12,810
ABOUT THIS.

641
00:26:12,810 --> 00:26:14,344
WELL, WE WERE VERY GRATIFIED TO

642
00:26:14,344 --> 00:26:18,982
FIND THAT IN RESPONSE TO A

643
00:26:18,982 --> 00:26:21,084
SEIZURE THE CONCENTRATION OF

644
00:26:21,084 --> 00:26:23,887
GPR55 RECEPTORS WAS GREATLY

645
00:26:23,887 --> 00:26:25,789
INCREASED AND THAT AFFECT WAS

646
00:26:25,789 --> 00:26:27,624
BLOCKED BY CBD, SO THIS IS NOT

647
00:26:27,624 --> 00:26:29,960
JUST YOUR COMMON GARDEN VARIETY

648
00:26:29,960 --> 00:26:31,929
RESPONSE WHERE THE RECEPTORS

649
00:26:31,929 --> 00:26:36,733
REMAIN THE SAME, AND THE

650
00:26:36,733 --> 00:26:38,268
SIGNALING THEY DO IS WHAT

651
00:26:38,268 --> 00:26:38,535
CHAIMPLES.

652
00:26:38,535 --> 00:26:40,370
HERE NOT ONLY IS THE SIGNALING

653
00:26:40,370 --> 00:26:42,239
CHAIVENLGING BUT ALSO THE NUMBER

654
00:26:42,239 --> 00:26:43,040
OF RECEPTORS THEMSELVES ARE

655
00:26:43,040 --> 00:26:45,943
CHANGING IN A SEIZURE DEPENDENT

656
00:26:45,943 --> 00:26:47,811
AND CBD DEPENDENT WAY THIS IS

657
00:26:47,811 --> 00:26:51,515
THE GROUP DATA SHOWING THAT IN

658
00:26:51,515 --> 00:26:55,285
CAC1 AND CA3, AND LESS

659
00:26:55,285 --> 00:26:57,588
PROMINENTLY IN DENTAIMIEROUS,

660
00:26:57,588 --> 00:26:58,689
THERE'S A CLEAR INCREASE IN THE

661
00:26:58,689 --> 00:27:07,331
LEVEL OF RECEPTOR WHICH IS

662
00:27:07,331 --> 00:27:07,998
REVERSED BY CBD.

663
00:27:07,998 --> 00:27:10,701
SO THIS MEANS THERE'S AN

664
00:27:10,701 --> 00:27:11,869
INHERENT LOOP BACK FEATURE

665
00:27:11,869 --> 00:27:15,005
BECAUSE THE NUMBER THAT'S

666
00:27:15,005 --> 00:27:15,806
RESPONDING IS INCREASED.

667
00:27:15,806 --> 00:27:18,375
AND LIKEWISE WHEN WE DID

668
00:27:18,375 --> 00:27:25,516
EXPERIMENTS USING RTPC R,

669
00:27:25,516 --> 00:27:27,084
AGAINST THE MRNA THAT ENCODES

670
00:27:27,084 --> 00:27:29,686
WITH THE SEIZURE, THIS ALSO

671
00:27:29,686 --> 00:27:30,888
DECODES AND DECREASED AND EVEN

672
00:27:30,888 --> 00:27:33,090
MORE REVERSED BY THE PRESENCE OF

673
00:27:33,090 --> 00:27:33,423
CBD.

674
00:27:33,423 --> 00:27:36,093
AS IF THERE WERE AN AMBIENT

675
00:27:36,093 --> 00:27:40,597
LEVEL OF LPL PRESENT IN THE

676
00:27:40,597 --> 00:27:42,699
SLICE, EVEN BEFORE CBD WAS

677
00:27:42,699 --> 00:27:50,140
APPLIED OR AN AMBIENT LEVEL OF

678
00:27:50,140 --> 00:27:50,941
THE RECEPTOR.

679
00:27:50,941 --> 00:27:52,175
SOPHISTICATED HOW ABOUT THE

680
00:27:52,175 --> 00:27:53,510
LIGAND, IS IT ALSO INFLUENCED BY

681
00:27:53,510 --> 00:27:57,614
THE FACT THAT YOU HAVE A

682
00:27:57,614 --> 00:27:57,848
SEIZURE?

683
00:27:57,848 --> 00:28:04,254
WELL WE MADE AN ACUTE SEIZURE

684
00:28:04,254 --> 00:28:05,622
WITH [INDISCERNIBLE], AND IT WAS

685
00:28:05,622 --> 00:28:07,357
ELEVATED BY THE SEIZURE AND MORE

686
00:28:07,357 --> 00:28:10,260
THAN REVERSED BY THE PRESENCE OF

687
00:28:10,260 --> 00:28:13,430
CBD, THIS WAS DONE BY MASS SPEC

688
00:28:13,430 --> 00:28:16,633
AGENTS AND OUR LIPID OMICS CORE

689
00:28:16,633 --> 00:28:20,103
AND I WANT TO POINT OUT THAT THE

690
00:28:20,103 --> 00:28:21,138
ISOFORM, PARTICULAR ISOFORM THAT

691
00:28:21,138 --> 00:28:26,310
IS ASHINGED IS THE 180 ISOFORM,

692
00:28:26,310 --> 00:28:29,012
18 CARBONS, 0 DOUBLE BONDS, THIS

693
00:28:29,012 --> 00:28:31,181
IS THE CLASSIC ALLELE FORM OF

694
00:28:31,181 --> 00:28:33,951
LPI THAT WAS THE VERY FORM THAT

695
00:28:33,951 --> 00:28:36,153
WAS INCREASED IN RESPONSE TO THE

696
00:28:36,153 --> 00:28:39,957
KNOCK OUT OF THE ENZYME THAT

697
00:28:39,957 --> 00:28:44,895
RECONVERTS THIS BACK INTO PI.

698
00:28:44,895 --> 00:28:47,531
SO SO THIS IS AN ALIGNMENT

699
00:28:47,531 --> 00:28:49,700
BETWEEN GENETICS AND THE

700
00:28:49,700 --> 00:28:50,701
BIOCHEMISTRY, THE BIOCHEMISTRY

701
00:28:50,701 --> 00:28:53,203
IN THE SLICE SAYS THAT EPILEPTIC

702
00:28:53,203 --> 00:28:54,371
SEIZURES REPRODUCE THE ACT THAT

703
00:28:54,371 --> 00:28:57,274
IS PRODUCED BY THE RESULT IN THE

704
00:28:57,274 --> 00:28:58,208
CONSANGUINEOUS FAMILIES AND I

705
00:28:58,208 --> 00:28:59,810
FIND THIS VERY SATISFYING

706
00:28:59,810 --> 00:29:02,446
BECAUSE IT PROVIDS SOME EVIDENCE

707
00:29:02,446 --> 00:29:05,916
THAT IT'S LPI AND NOT PI THAT IS

708
00:29:05,916 --> 00:29:09,453
THE KEY FACTOR UNDERLYING THE

709
00:29:09,453 --> 00:29:14,257
MANIFESTATIONS OF AUTISM,

710
00:29:14,257 --> 00:29:14,958
EPILEPSY AND INTELLECTUAL

711
00:29:14,958 --> 00:29:16,460
DISABILITY IN THOSE FAMILIES.

712
00:29:16,460 --> 00:29:18,528
SO TO SUMMARIZE WHAT I TOLD YOU

713
00:29:18,528 --> 00:29:19,196
SO FAR.

714
00:29:19,196 --> 00:29:27,638
LPI ACTS ON A RECEPTOR, THE

715
00:29:27,638 --> 00:29:34,277
RECEPTOR ACTS AS THE INVITATION

716
00:29:34,277 --> 00:29:37,981
AND SIMULTANEOUSLY SHUT DOWN

717
00:29:37,981 --> 00:29:40,450
THE, LPI, IF YOU PRESS DOWN ON

718
00:29:40,450 --> 00:29:41,618
THE ACCELERATOR AND LET GO OF

719
00:29:41,618 --> 00:29:44,354
THE BREAK, YOUR CAR IS GOING TO

720
00:29:44,354 --> 00:29:45,922
GO FASTER.

721
00:29:45,922 --> 00:29:47,524
THAT PRODUCES HYPER-ACTIVITY,

722
00:29:47,524 --> 00:29:52,763
AND IN TURN, THE HYPER-ACTIVITY

723
00:29:52,763 --> 00:29:58,101
CAUSES AN INCREASE IN LPI-GPCR,

724
00:29:58,101 --> 00:29:59,736
AND EVERY ARROW IS POINTING

725
00:29:59,736 --> 00:30:01,238
UPWARD, IT'S A POSITIVE FEEDBACK

726
00:30:01,238 --> 00:30:04,041
LOOP ALL THE WAY DOWN THE LINE

727
00:30:04,041 --> 00:30:05,308
AND THIS EXPLAINS WHY EPILEPSY

728
00:30:05,308 --> 00:30:07,744
CAN BE A RUN AWAY PHENOMENA AND

729
00:30:07,744 --> 00:30:11,415
IT IN FACT, IT CAN REOCCUR.

730
00:30:11,415 --> 00:30:14,885
AND CBD COMES ALONG, BLOCKS THE

731
00:30:14,885 --> 00:30:16,720
RECEPTOR, PREVENTS THE EFFECT OF

732
00:30:16,720 --> 00:30:19,523
LPI FROM ACTING ON GPR55,

733
00:30:19,523 --> 00:30:21,958
ANTAGONIZES THE INCREASED LEVEL

734
00:30:21,958 --> 00:30:27,597
OF GPR55, DECREASES THE LEVEL OF

735
00:30:27,597 --> 00:30:28,899
EXCITATION, DECREASES SEIZURES,

736
00:30:28,899 --> 00:30:29,599
PREVENTS HYPER-ACTIVITY AND

737
00:30:29,599 --> 00:30:31,902
BASIC LYE PUTS OUT THE FIRE,

738
00:30:31,902 --> 00:30:34,071
PUTS OUT THE REGENERATIVE

739
00:30:34,071 --> 00:30:39,376
PROCESS, OR SO WE CLAIMED.

740
00:30:39,376 --> 00:30:41,078
LET'S LOOK AT MORE EVIDENCE FOR

741
00:30:41,078 --> 00:30:43,480
THIS BY SEEING WHETHER SEIZURES

742
00:30:43,480 --> 00:30:45,248
CHANGE THE LEVEL OF GPR55 AND

743
00:30:45,248 --> 00:30:49,853
THE TIME COURSE AND DYNAMICS OF

744
00:30:49,853 --> 00:30:50,053
THAT.

745
00:30:50,053 --> 00:30:52,422
SO IN THESE EXPERIMENTS

746
00:30:52,422 --> 00:30:59,896
PERFORMED BY HELEN SCHARFMAN,

747
00:30:59,896 --> 00:31:05,569
AND OTHERS COLLEAGUES IN THE NYU

748
00:31:05,569 --> 00:31:06,703
PSYCHIATRY, THIS ACTIVATES

749
00:31:06,703 --> 00:31:08,705
CERTAIN TYPES OF CERTAIN TYPES

750
00:31:08,705 --> 00:31:11,374
OF GLUTAMATE RECEPTORS AND

751
00:31:11,374 --> 00:31:12,375
PRODUCES EPILESY VERY HIPPO

752
00:31:12,375 --> 00:31:14,678
CAMPALLY BASED AND IF WE INDUCE

753
00:31:14,678 --> 00:31:19,416
A SEIZURE BY TREATMENT WITH

754
00:31:19,416 --> 00:31:20,517
[INDISCERNIBLE] AND WAIT 48

755
00:31:20,517 --> 00:31:23,420
HOURS AND THEN ASSESS THE LEVEL

756
00:31:23,420 --> 00:31:26,156
OF RECEPTOR USING EITHER PC R OR

757
00:31:26,156 --> 00:31:26,957
IMMUNO CYTOCHEMMISTRY, CAN YOU

758
00:31:26,957 --> 00:31:30,727
SEE A VERY CLEAR INCREASE IN THE

759
00:31:30,727 --> 00:31:34,231
LEVEL OF GPR 55.

760
00:31:34,231 --> 00:31:36,066
WHICH IS PREVENTIVE IF YOU GIVE

761
00:31:36,066 --> 00:31:39,970
CBD AT THE SAME TIME THAT YOU

762
00:31:39,970 --> 00:31:40,537
GIVE KA.

763
00:31:40,537 --> 00:31:42,873
SO 48 HOURS AFTER THE SEIZURE,

764
00:31:42,873 --> 00:31:45,208
THERE'S A BIOCHEMICAL TRAIL,

765
00:31:45,208 --> 00:31:47,410
MAKING THE SLICE MORE

766
00:31:47,410 --> 00:31:49,012
SUSCEPTIBILITY TO HAVING ANOTHER

767
00:31:49,012 --> 00:31:51,248
SEIZURE BECAUSE THERE'S NOR

768
00:31:51,248 --> 00:31:52,082
GPR55 PRESENT.

769
00:31:52,082 --> 00:31:55,252
AND THIS WAS TRUE ONCE AGAIN, IN

770
00:31:55,252 --> 00:31:57,554
THE CAC1 AND 3 REGIONS IN BOTH

771
00:31:57,554 --> 00:31:57,754
CASES.

772
00:31:57,754 --> 00:32:01,658
THERE WAS A CLEAR ELEVATION IN

773
00:32:01,658 --> 00:32:01,892
GPR55.

774
00:32:01,892 --> 00:32:05,562
NOW IF IT'S THE CASE, THAT 1

775
00:32:05,562 --> 00:32:07,531
SEIZURE, LAYS A TRAIL, LEAVES A

776
00:32:07,531 --> 00:32:10,300
TRAIL BEHIND AND LEAVES A

777
00:32:10,300 --> 00:32:11,234
PREDISPOSITION FOR A SECOND

778
00:32:11,234 --> 00:32:12,068
SEIZURE, WE SHOULD BE ABLE TO

779
00:32:12,068 --> 00:32:15,172
COME IN WITH A SECOND PULSE OF

780
00:32:15,172 --> 00:32:16,940
KA, AND THEN LOOK TO SEE WHETHER

781
00:32:16,940 --> 00:32:21,511
THAT PRODUCES A HIGHER INCIDENCE

782
00:32:21,511 --> 00:32:30,353
OF SEIZURES, SO WE TREATED THE

783
00:32:30,353 --> 00:32:32,923
TISSUE OF THE ANIMALS WITH A LOW

784
00:32:32,923 --> 00:32:35,725
DOSE OF KA, AND 1 NOT ENOUGH TO

785
00:32:35,725 --> 00:32:36,660
PRODUCE A SEIZURE AND

786
00:32:36,660 --> 00:32:38,395
NONETHELESS WE SAW THAT WE CAME

787
00:32:38,395 --> 00:32:40,030
IN WITH A SECOND DOSE OF KA, THE

788
00:32:40,030 --> 00:32:41,898
SECOND DOSE WAS EFFECTIVE 14 OUT

789
00:32:41,898 --> 00:32:44,201
OF 15 TIMES TO PRODUCE THE

790
00:32:44,201 --> 00:32:45,802
SEIZURE TO THE SECOND ROUND,

791
00:32:45,802 --> 00:32:50,006
THIS IS LIKE PAIRED PULSE

792
00:32:50,006 --> 00:32:52,809
FACILITATION, 2 POSTS OF KA,

793
00:32:52,809 --> 00:32:54,377
FITTER 1 DOESN'T DO MUCH, BUT

794
00:32:54,377 --> 00:32:58,882
THE SECOND 1 DOES A LOT, NOW IF

795
00:32:58,882 --> 00:33:00,750
WE TREAT WITH CBD JUST BEFORE

796
00:33:00,750 --> 00:33:03,720
THE SECOND DOSE OF KA, THEN WE

797
00:33:03,720 --> 00:33:04,921
PREVENT THE SEIZURES, THATTED BE

798
00:33:04,921 --> 00:33:06,623
EXPECTED BUT MORE IMPORTANTLY IF

799
00:33:06,623 --> 00:33:10,694
WE TREAT WITH CBD, DURING THE

800
00:33:10,694 --> 00:33:13,330
FIRST EXPOSURE TO KA, THEN

801
00:33:13,330 --> 00:33:14,698
LIKELIHOOD OF SEEING SEIZURES IS

802
00:33:14,698 --> 00:33:15,298
CUT IN HALF.

803
00:33:15,298 --> 00:33:17,734
THAT MEANS THAT THE TRAIL LEFT

804
00:33:17,734 --> 00:33:20,203
BEHIND BY THE FIRST SEIZURE IS

805
00:33:20,203 --> 00:33:21,738
DEPENDENT ON WHETHER CBD WAS

806
00:33:21,738 --> 00:33:24,441
PRESENT, AND SO THIS FITS WITH

807
00:33:24,441 --> 00:33:28,144
THE HYPOTHESIS, THAT UNCHECKED

808
00:33:28,144 --> 00:33:32,415
SEIZURES, BEGET FURTHER SEIZURE,

809
00:33:32,415 --> 00:33:36,319
WE TESTED THIS AGAIN BY LOOKING

810
00:33:36,319 --> 00:33:38,722
NOT AT SEIZURE SUSEPTIBILITY BUT

811
00:33:38,722 --> 00:33:40,023
LOOKING AT EXCITATORY MINIS TO

812
00:33:40,023 --> 00:33:41,925
SEE THE SAME TYPE OF EFFECT

813
00:33:41,925 --> 00:33:42,125
THERE.

814
00:33:42,125 --> 00:33:44,027
WE SHOWED THE EECT OF WELL, PI

815
00:33:44,027 --> 00:33:45,562
IN THE ABSENCE OF SEIZURE AND

816
00:33:45,562 --> 00:33:46,963
CONTROL ISSUE ITS.

817
00:33:46,963 --> 00:33:48,632
IT INCREASED THE FREQUENCIES OF

818
00:33:48,632 --> 00:33:51,635
MINIS AND WE COMPARED THAT WITH

819
00:33:51,635 --> 00:33:52,802
WHAT HAPPENED IN TISSUE TAKEN

820
00:33:52,802 --> 00:33:55,939
FROM MICE THAT HAD BEEN DRIVEN

821
00:33:55,939 --> 00:33:59,943
TO SEIZURES BY LITHIUM

822
00:33:59,943 --> 00:34:02,212
PILOCARPINE, YET ANOTHER WAY OF

823
00:34:02,212 --> 00:34:05,515
MAKING SEIZURES AND 1 THAT

824
00:34:05,515 --> 00:34:06,917
EPILEAPTOLOGYISTS SWEAR BY

825
00:34:06,917 --> 00:34:08,285
BECAUSE IT WILL PRODUCE CHRONIC

826
00:34:08,285 --> 00:34:09,152
SEIZURES OVER AND OVER AGAIN AND

827
00:34:09,152 --> 00:34:10,687
HERE YOU CAN SEE THAT THE EFFECT

828
00:34:10,687 --> 00:34:12,689
OF LPI IS GREATLY ENHANCED, MORE

829
00:34:12,689 --> 00:34:14,758
THAN DOUBLED IN SIZE AND EVEN

830
00:34:14,758 --> 00:34:18,028
AFTER YOU WASH OFF THE LPI, THE

831
00:34:18,028 --> 00:34:18,962
ENHANCEMENT OF MANY FREQUENCY IS

832
00:34:18,962 --> 00:34:19,229
SUSTAINED.

833
00:34:19,229 --> 00:34:24,834
SO THIS IS ALMOST LIKE LTP IN

834
00:34:24,834 --> 00:34:26,937
THAT A SYNAPTIC INPUT IS

835
00:34:26,937 --> 00:34:29,306
PROLONGED IN ITS EFFICACY.

836
00:34:29,306 --> 00:34:31,274
AND SO THIS IS AN INDICATION

837
00:34:31,274 --> 00:34:34,678
THAT THE CELLULAR LEVEL, THAT 1

838
00:34:34,678 --> 00:34:36,379
SEIZURE LEAVES BEHIND A TRAIL

839
00:34:36,379 --> 00:34:38,581
THAT MAKES IT MORE LIKELY TO SEE

840
00:34:38,581 --> 00:34:41,117
A SECOND SEIZURE, AND WE SAW A

841
00:34:41,117 --> 00:34:44,754
SIMILAR ACCENTUATION OF THE LPI

842
00:34:44,754 --> 00:34:47,857
INDUCED DECREASE IN MANY IPSC

843
00:34:47,857 --> 00:34:48,758
AMPLITUDE.

844
00:34:48,758 --> 00:34:50,961
ONCE AGAIN THAT'S POST SYNAPTIC,

845
00:34:50,961 --> 00:34:53,863
THIS POST IS PRESYNAPTIC BUT IN

846
00:34:53,863 --> 00:34:55,598
BOTH CASES CHRONIC SEIZURES MAKE

847
00:34:55,598 --> 00:34:56,900
THE EFFECT BIGGER, NOT

848
00:34:56,900 --> 00:35:00,170
UNEXPECTEDLY BECAUSE THE NUMBER

849
00:35:00,170 --> 00:35:03,039
OF IMRKS PR 55 RECEPTORS IS

850
00:35:03,039 --> 00:35:04,307
INCREASED AND THIS EXPERIMENT

851
00:35:04,307 --> 00:35:07,210
WAS DONE BY MICHAEL BASSELOT,

852
00:35:07,210 --> 00:35:14,517
AND WE HAD HELP FROM AUSTIN

853
00:35:14,517 --> 00:35:16,152
UNIVERSITY DOING CONTROL

854
00:35:16,152 --> 00:35:18,421
EXPERIMENTS THAT WE COULD

855
00:35:18,421 --> 00:35:19,856
CONTROL THIS BY CHRONIC

856
00:35:19,856 --> 00:35:21,124
TREATMENT WITH CBD, SO IT ALL

857
00:35:21,124 --> 00:35:25,095
FITS WITH THE HYPOTHESIS NAMELY

858
00:35:25,095 --> 00:35:27,197
THAT CBD IS A VERY CLEVER DRUG

859
00:35:27,197 --> 00:35:31,835
THIS IN THE WAY THAT AFFECTS

860
00:35:31,835 --> 00:35:33,837
SEIZURES AND IT PREVENTS THE

861
00:35:33,837 --> 00:35:34,804
POSITIVE FEEDBACK ASPECTS OF THE

862
00:35:34,804 --> 00:35:36,873
CIRCUIT AND TAKES OUT WHAT IS

863
00:35:36,873 --> 00:35:39,109
VERY CHARACTERISTIC OF EPILEPSY,

864
00:35:39,109 --> 00:35:42,512
NAMELY THAT 1 SEIZURE, CAN LEAVE

865
00:35:42,512 --> 00:35:43,847
BEHIND A TENDENCY TO HAVE

866
00:35:43,847 --> 00:35:46,750
ANOTHER SEIZURE AT A LATER TIME.

867
00:35:46,750 --> 00:35:50,120
NOW, SO FAR, I FOCUSED ON

868
00:35:50,120 --> 00:35:52,989
SYNAPTIC TARGETS OF CBD, HOW

869
00:35:52,989 --> 00:35:54,791
ABOUT ION CHANNELS AND ARE THEY

870
00:35:54,791 --> 00:35:56,059
INVOFFED.

871
00:35:56,059 --> 00:35:58,795
SO WE LOOKED THEN AND THIS IS

872
00:35:58,795 --> 00:36:01,364
SIMON CHAIMER LAND THIS, IS 2

873
00:36:01,364 --> 00:36:02,966
MAJOR CATEGORIES OF NEURON,

874
00:36:02,966 --> 00:36:04,868
WE'RE NOT GOING DOWN AS FINE AS

875
00:36:04,868 --> 00:36:06,703
ALL THE VARIOUS SUBTYPES, WE'RE

876
00:36:06,703 --> 00:36:09,105
JUST GOING TO DISTINGUISH

877
00:36:09,105 --> 00:36:10,140
BETWEEN FAST SPIKING

878
00:36:10,140 --> 00:36:12,208
INTERNEURONS AND REGULAR SPIKING

879
00:36:12,208 --> 00:36:13,276
INTERNEURONS THAT ARE

880
00:36:13,276 --> 00:36:15,445
CHARACTERIZED BY BEING RICH IN

881
00:36:15,445 --> 00:36:17,113
THE MARKER SOPHISTICATED

882
00:36:17,113 --> 00:36:17,547
MATOSTAT.

883
00:36:17,547 --> 00:36:19,349
THEY HAVE VERY DIFFERENT

884
00:36:19,349 --> 00:36:21,518
MORPHOLOGIES, THE PV NEURONS ARE

885
00:36:21,518 --> 00:36:23,386
VERY OFTEN BASKET CELLS WITH

886
00:36:23,386 --> 00:36:25,422
CELL BODIES AND LOTS OF AXONAL

887
00:36:25,422 --> 00:36:28,291
RAM IIVES IN THE PARAMETRAL

888
00:36:28,291 --> 00:36:36,199
LAYER WHERE THEY ACT AS A DAMPER

889
00:36:36,199 --> 00:36:38,802
ON PARAMETER EXCITATION, AND WE

890
00:36:38,802 --> 00:36:41,237
CAN SCHEMEATIZE THEM IN TALKING

891
00:36:41,237 --> 00:36:43,773
ABOUT FEET FORWARD INHIBITION

892
00:36:43,773 --> 00:36:47,043
WHICH OCCURS WHEN IT FIRES A

893
00:36:47,043 --> 00:36:50,914
NEURON AND SO THAT'S FEET

894
00:36:50,914 --> 00:36:51,781
FORWARD IPT GREATER HIB

895
00:36:51,781 --> 00:36:52,816
THORSITION, AND AFTER IT FIRES

896
00:36:52,816 --> 00:36:55,351
OR IF IT FIRE SAYS, THE

897
00:36:55,351 --> 00:36:56,019
SOPHISTICATED MAT'S STATIN

898
00:36:56,019 --> 00:36:57,587
NEURON IS CAUSED TO RELEASE

899
00:36:57,587 --> 00:37:00,657
GABBA FAR AWAY FROM THE CELL

900
00:37:00,657 --> 00:37:01,291
BODY, TRANSFERRING ACTIVITIES

901
00:37:01,291 --> 00:37:03,159
AND PROJECTS INPUT AND 1 LAYER

902
00:37:03,159 --> 00:37:07,630
OF THE HISM HIPPOCAMPUS AND

903
00:37:07,630 --> 00:37:08,898
INHIBITORY REGION IN THE

904
00:37:08,898 --> 00:37:09,199
HIPPOCAMPUS.

905
00:37:09,199 --> 00:37:11,668
AND THIS IS HEAVILY STUDIED BY

906
00:37:11,668 --> 00:37:14,003
CHRIS Mc MAIN, KEN PELKY AND

907
00:37:14,003 --> 00:37:15,638
THEIR COLLEAGUES HERE AT NIH AND

908
00:37:15,638 --> 00:37:17,240
THEY'VE GONE ON TO EVEN MORE

909
00:37:17,240 --> 00:37:20,076
TYPES BUT FOR NOW THIS, IS

910
00:37:20,076 --> 00:37:21,544
ENOUGH TO MAKE THE POINT I'M

911
00:37:21,544 --> 00:37:29,519
GOING TO MAKE THAT IS THE

912
00:37:29,519 --> 00:37:31,254
[INDISCERNIBLE] WHEREAS THE

913
00:37:31,254 --> 00:37:32,322
FEEDBACK INHIBITION HAS OTHER

914
00:37:32,322 --> 00:37:34,257
PURPOSE, SO WHAT HAPPEN WHEN IS

915
00:37:34,257 --> 00:37:38,261
YOU TREAT WITH CBD TO THESE

916
00:37:38,261 --> 00:37:39,529
FORMS OF INHIBITION?

917
00:37:39,529 --> 00:37:41,831
WELL, HERE'S A MORE

918
00:37:41,831 --> 00:37:43,066
PHYSIOLOGICAL INPUT, A SHORT

919
00:37:43,066 --> 00:37:46,503
TRAIN OF ACTION POTENTIALS AT 50

920
00:37:46,503 --> 00:37:50,039
HURTS SO THE ACTION POTENTIALS

921
00:37:50,039 --> 00:37:51,074
ARE 20 MILLISECONDS APART

922
00:37:51,074 --> 00:37:52,609
APPROXIMATE AND WE WILL GIVE

923
00:37:52,609 --> 00:37:52,942
THEM 5.

924
00:37:52,942 --> 00:37:55,545
SO THIS IS TYPICAL OF A BURST OF

925
00:37:55,545 --> 00:37:59,149
FIRING IN THE HIPPOCAMPUS IN

926
00:37:59,149 --> 00:38:00,450
RESPONSE TO SYSTEMS NEUROSCIENCE

927
00:38:00,450 --> 00:38:00,917
LEVEL ACTIVITY.

928
00:38:00,917 --> 00:38:03,920
IN THE CONTROL IN THIS SLICE,

929
00:38:03,920 --> 00:38:06,756
THERE MAY BE 1 SPIKE, MAYBE 0

930
00:38:06,756 --> 00:38:09,726
SPIKES BUT NOT VERY MANY SPIKES

931
00:38:09,726 --> 00:38:12,195
IN THE PRESENCE OF CBD, ALL THE

932
00:38:12,195 --> 00:38:13,596
SPIKES ARE COMPLETELY GONE AND

933
00:38:13,596 --> 00:38:17,200
ON AVERAGE, THERE IS A VERY

934
00:38:17,200 --> 00:38:19,302
PROMINENT CHANGE IN THE STIMULUS

935
00:38:19,302 --> 00:38:21,070
NUMBER DEPENDENTS OF WHETHER

936
00:38:21,070 --> 00:38:26,476
THERE'S AN ACTION POTENTIAL OR

937
00:38:26,476 --> 00:38:29,913
NOT, EXCITABILITY IS GREATLY

938
00:38:29,913 --> 00:38:31,781
DECREASED IN THE PARIETAL

939
00:38:31,781 --> 00:38:32,015
NEURON.

940
00:38:32,015 --> 00:38:33,850
WHY DOES THIS OCCUR IN LET'S

941
00:38:33,850 --> 00:38:36,252
LOOK AT USING STIEWMUE LIE THAT

942
00:38:36,252 --> 00:38:37,554
ARE WEAK ENOUGH NOT TO PRODUCE

943
00:38:37,554 --> 00:38:40,690
ANY SPIKES SO WE CAN LOOK AT THE

944
00:38:40,690 --> 00:38:43,026
COMPOUND SYNAPTIC POTENTIAL THAT

945
00:38:43,026 --> 00:38:44,527
ARISES FROM EXCITATORY

946
00:38:44,527 --> 00:38:45,261
TRANSMISSION AND INHIBITORY

947
00:38:45,261 --> 00:38:47,830
TRANSMISSION ALL OCCURS AT THE

948
00:38:47,830 --> 00:38:48,598
SAME TIME.

949
00:38:48,598 --> 00:38:51,568
IN THE ABSENCE OF CBD, WE SEE A

950
00:38:51,568 --> 00:38:53,536
GRADUAL BUILD UP OF

951
00:38:53,536 --> 00:38:55,271
DEPOLARIZATION, THIS IS VERY

952
00:38:55,271 --> 00:38:56,339
PHYSIOLOGICAL, THIS IS WHAT

953
00:38:56,339 --> 00:38:58,641
WOULD MAKE THE NEURON REACH THE

954
00:38:58,641 --> 00:38:59,909
THRESHOLD, ONLY WE'RE NOT QUIT

955
00:38:59,909 --> 00:39:02,111
HITTING THRESHOLD HERE SO WE CAN

956
00:39:02,111 --> 00:39:04,747
ANALYZE THE SYNAPTIC EVENTS IN

957
00:39:04,747 --> 00:39:07,417
RESPONSE TO CBD, THE

958
00:39:07,417 --> 00:39:10,119
NETDEPOLARIZATION IS STRONGLY

959
00:39:10,119 --> 00:39:12,422
DECREASED, CONSISTENT WITH THE

960
00:39:12,422 --> 00:39:14,390
LOWERING OF THE NUMBER OF ACTION

961
00:39:14,390 --> 00:39:15,592
POTENTIALS AND THIS IS GROUP

962
00:39:15,592 --> 00:39:17,760
DATA SHOWING THE SAME THING.

963
00:39:17,760 --> 00:39:20,263
NOW WHAT HAPPENS IF WE KNOCK OUT

964
00:39:20,263 --> 00:39:20,797
THE RECEPTOR?

965
00:39:20,797 --> 00:39:23,166
WELL, IN THE ABSENCE OF THE

966
00:39:23,166 --> 00:39:26,703
RECEPTOR THIS EFFECT IS

967
00:39:26,703 --> 00:39:27,937
COMPLETELY GONE.

968
00:39:27,937 --> 00:39:30,039
WHAT HAPPENS IF WE MIMIC THIS

969
00:39:30,039 --> 00:39:36,980
WITH AN ARTIFICIAL AGENT, NOT A

970
00:39:36,980 --> 00:39:40,416
PH ITOCANNABOID OF THE RECEPTOR

971
00:39:40,416 --> 00:39:42,085
BUT IT'S SELECTIVELY BEEN

972
00:39:42,085 --> 00:39:43,853
ENGINEERED FOR THE RECEPTOR IT'S

973
00:39:43,853 --> 00:39:46,089
CALLED CID AND AT A LOW

974
00:39:46,089 --> 00:39:47,490
CONCENTRATION THIS MIMICS THE

975
00:39:47,490 --> 00:39:50,059
EFFECTS OF CBD, IN PRESENCE OF

976
00:39:50,059 --> 00:39:53,162
CID, WE APPLY CBD, AND NOW CBD

977
00:39:53,162 --> 00:39:53,763
HAS NO ADDITIONAL CENTER FOR

978
00:39:53,763 --> 00:39:54,197
EXCELLENCE ON AGING.

979
00:39:54,197 --> 00:39:57,233
SO THE EFFECT OF CBD HAS BEEN

980
00:39:57,233 --> 00:40:01,604
OCCLUDED BY THE PRESENCE OF CID,

981
00:40:01,604 --> 00:40:03,072
ONCE AGAIN RECONFIRMING THE IDEA

982
00:40:03,072 --> 00:40:05,642
THAT IS DUE TO THE GPR55

983
00:40:05,642 --> 00:40:05,908
RECEPTOR.

984
00:40:05,908 --> 00:40:07,510
WHETHER YOU KNOCK OUT THE

985
00:40:07,510 --> 00:40:08,578
RECEPTOR ASK ILLUMINATE THE

986
00:40:08,578 --> 00:40:10,813
EFFECT OR STIMULATE THE RECEPTOR

987
00:40:10,813 --> 00:40:12,415
USING CID AND GET THE FULL

988
00:40:12,415 --> 00:40:15,151
EFFECT, EITHER WAY, IT'S VERY

989
00:40:15,151 --> 00:40:17,120
CONVINCING EVIDENT THIS EFFECT

990
00:40:17,120 --> 00:40:20,189
ON EXCITABILITY AND SYNAPTIC

991
00:40:20,189 --> 00:40:22,025
TRANSMISSION IS GPR 55

992
00:40:22,025 --> 00:40:22,292
DEPENDENT.

993
00:40:22,292 --> 00:40:25,261
THE KEY EXPERIMENT IS TO COMPARE

994
00:40:25,261 --> 00:40:29,732
THE RESULTS OF EXCITATORY

995
00:40:29,732 --> 00:40:31,467
TRANSMISSION ALONE OR EXCITATORY

996
00:40:31,467 --> 00:40:32,869
TRANSMISSION WITH GABBA

997
00:40:32,869 --> 00:40:38,207
RECEPTORS BLOCKED SO NORMALLY WE

998
00:40:38,207 --> 00:40:40,543
HAVE BOTH GLAITA MATE RECEPTORS

999
00:40:40,543 --> 00:40:43,079
AND GABBA RECEPTORS, IF WE BLOCK

1000
00:40:43,079 --> 00:40:46,749
GABBA RECEPTORS NOW ONCE AGAIN

1001
00:40:46,749 --> 00:40:47,917
CBD GOES COMLITELY AWAY.

1002
00:40:47,917 --> 00:40:49,852
THAT MEANS THIS WAS NOT AN

1003
00:40:49,852 --> 00:40:51,354
EFFECT ON THE EXCITATORY TRAN

1004
00:40:51,354 --> 00:40:54,157
MISSION, IT WAS AN EFFECT ON

1005
00:40:54,157 --> 00:40:55,525
INHIBITORY TRANSMISSION THAT

1006
00:40:55,525 --> 00:40:59,929
COUNTERACTED THE EFFECT OF THE

1007
00:40:59,929 --> 00:41:00,763
EXCITATORY TRANSMISSION, SO WE

1008
00:41:00,763 --> 00:41:08,738
SEE A COMPLETE BUILD UP  WITHOUT

1009
00:41:08,738 --> 00:41:10,373
ANY IPSCs, SO THIS TELLS US

1010
00:41:10,373 --> 00:41:12,241
THAT IT'S MEDIATED BY THE GABBA

1011
00:41:12,241 --> 00:41:15,978
SERNLGIC SYSTEM AND NOT THE

1012
00:41:15,978 --> 00:41:18,047
GLUTEA MA TERNLGIC SYSTEM, SO

1013
00:41:18,047 --> 00:41:19,082
WHICH NEURON IS RESPONSIBLE FOR

1014
00:41:19,082 --> 00:41:19,349
THIS.

1015
00:41:19,349 --> 00:41:22,285
THE OBVIOUS POSSIBILITY IS THAT

1016
00:41:22,285 --> 00:41:24,954
PV NEURONS WHICH MEDIATE FEET

1017
00:41:24,954 --> 00:41:26,756
FORWARD INHIBITION ARE WRONG.

1018
00:41:26,756 --> 00:41:29,192
SO TO STUDY THIS WE CAN NOW

1019
00:41:29,192 --> 00:41:30,693
RECORD FROM PC NEURONS AND SO

1020
00:41:30,693 --> 00:41:33,763
THIS IS NOT THE SPIKING IN THE

1021
00:41:33,763 --> 00:41:35,665
EXCITATORY NEURONS, AND THE

1022
00:41:35,665 --> 00:41:38,301
EXCITATORY NEURONS AND LOW AND

1023
00:41:38,301 --> 00:41:40,603
BEHOLD, CBD, GREATLY INCREASES

1024
00:41:40,603 --> 00:41:43,706
THE FIRING, MAYBE 3 FOLD, SO THE

1025
00:41:43,706 --> 00:41:44,774
PV NEURONS INSTEAD OF FIRING

1026
00:41:44,774 --> 00:41:47,443
EVERY ONCE IN A WHILE FIRE

1027
00:41:47,443 --> 00:41:49,712
ALMOST NEARLY ALL THE TIME AND

1028
00:41:49,712 --> 00:41:51,948
THIS EFFECT IS MIMICKED BY CID,

1029
00:41:51,948 --> 00:41:54,984
SHOWING ONCE AGAIN THAT IT'S DUE

1030
00:41:54,984 --> 00:41:56,319
TO GPR 55.

1031
00:41:56,319 --> 00:42:02,625
SO, NOW WE HAVE AN EFFECT OF CBD

1032
00:42:02,625 --> 00:42:04,127
ON THE INHIBITORY NEURON ITSELF,

1033
00:42:04,127 --> 00:42:05,928
NOT ONLY ON THE INHIBITORY

1034
00:42:05,928 --> 00:42:07,897
NEURON BUT THE VERY INHIBITORY

1035
00:42:07,897 --> 00:42:10,933
NEURON THAT IS MOST

1036
00:42:10,933 --> 00:42:12,301
STRATEGICALLY LOCATED AND PLACED

1037
00:42:12,301 --> 00:42:20,843
IN THE CIRCUIT TO QUELLCH ACTUAL

1038
00:42:20,843 --> 00:42:22,311
POTENTIAL PROPAGATION.

1039
00:42:22,311 --> 00:42:25,081
HOW ABOUT SST NEURONS, WE SEE

1040
00:42:25,081 --> 00:42:26,616
THE OPPOSITE, INSTEAD OF THESE

1041
00:42:26,616 --> 00:42:28,684
NEURONS FIRING MORE TO INCREASE

1042
00:42:28,684 --> 00:42:30,620
INHIBITION, THEY ARE FIRING LESS

1043
00:42:30,620 --> 00:42:37,059
AND THAT EFFECT IS ALSO MIMICKED

1044
00:42:37,059 --> 00:42:37,293
BY CID.

1045
00:42:37,293 --> 00:42:39,195
SO THE 2 INTERNEURON TYPES ARE

1046
00:42:39,195 --> 00:42:42,532
AFFECTED IN OPPOSITE DIRECTIONS.

1047
00:42:42,532 --> 00:42:43,733
WHAT IS THIS DUE TO?

1048
00:42:43,733 --> 00:42:46,235
IS IT DUE TO THE EXCITATORY

1049
00:42:46,235 --> 00:42:49,038
TRANSMISSION OR DUE TO INTRINSIC

1050
00:42:49,038 --> 00:42:49,972
EXCITABILITY, BECAUSE REMEMBER

1051
00:42:49,972 --> 00:42:53,276
WE'RE FIRING SPIKES HERE, WE'RE

1052
00:42:53,276 --> 00:42:54,343
DRIEBING THE PROBABILITY OF

1053
00:42:54,343 --> 00:42:56,212
SPIKES, SO THIS SHOW WHAT IS

1054
00:42:56,212 --> 00:42:58,815
HAPPENS IF YOU DEPOLARIZE, USING

1055
00:42:58,815 --> 00:43:01,784
THE CURRENT PATCH CLAMP

1056
00:43:01,784 --> 00:43:02,351
ELECTRODE BYPASSING INAPTIC

1057
00:43:02,351 --> 00:43:05,021
TRANSMISSION TO MAKE THE NEURON

1058
00:43:05,021 --> 00:43:07,657
FIRE SPIKES, HERE'S A FAST

1059
00:43:07,657 --> 00:43:09,091
SPIKING INTERFER NEURON AND

1060
00:43:09,091 --> 00:43:10,460
RESPONSE TO CBD, THE ACTUAL

1061
00:43:10,460 --> 00:43:11,627
POTENTIAL FETAL COMPARTMENT

1062
00:43:11,627 --> 00:43:13,963
FERENCEY GOES UP SIGNIFICANTLY,

1063
00:43:13,963 --> 00:43:15,798
PARTICULARLY PROMINENTLY AT

1064
00:43:15,798 --> 00:43:18,968
SMALL CURRENT INJECTIONS, SO CBD

1065
00:43:18,968 --> 00:43:21,504
ENHANCES THE INTRINSIC

1066
00:43:21,504 --> 00:43:23,973
PROPERTIES OF FIRING OF PV

1067
00:43:23,973 --> 00:43:26,075
NEURONS, IT HAS THE OPPOSITE

1068
00:43:26,075 --> 00:43:27,343
EFFECT ON SST NEURON.

1069
00:43:27,343 --> 00:43:30,880
SO THIS IS VERY CLEVER BECAUSE

1070
00:43:30,880 --> 00:43:31,914
IT'S ENHANCING THE EXCITABILITY

1071
00:43:31,914 --> 00:43:37,119
OF THE VERY FIEWRON THAT IS BEST

1072
00:43:37,119 --> 00:43:40,723
POSITIONS TO MEDIATE FEET

1073
00:43:40,723 --> 00:43:41,891
FORWARD INTERMISSION EMPLOY NOW

1074
00:43:41,891 --> 00:43:43,659
WE TESTED SODIUM EFFECTS OF

1075
00:43:43,659 --> 00:43:46,729
THIS, ON THE HYPOTHESIS, THIS

1076
00:43:46,729 --> 00:43:48,698
MIGHT INVOLVE ENHANCEMENT OF

1077
00:43:48,698 --> 00:43:50,433
SODIUM CARBONS AND THE

1078
00:43:50,433 --> 00:43:53,970
HYPOTHESIS WOULD BE THAT CBD

1079
00:43:53,970 --> 00:43:55,238
COULD PREVENT ENDOGENOUS DOWN

1080
00:43:55,238 --> 00:43:57,840
REGULATION OF SODIUM CURRENTS

1081
00:43:57,840 --> 00:44:02,645
MEDIATED BY CONVENTIONAL

1082
00:44:02,645 --> 00:44:03,913
SIGNALING PATHWAYS, STUDIED BY

1083
00:44:03,913 --> 00:44:05,281
[INDISCERNIBLE] AND JIM

1084
00:44:05,281 --> 00:44:07,116
[INDISCERNIBLE], AND IF THERE

1085
00:44:07,116 --> 00:44:09,785
WAS A TONIC AMOUNT OF LPI DOWN

1086
00:44:09,785 --> 00:44:12,288
REGULATING THE SODIUM CURRENT,

1087
00:44:12,288 --> 00:44:14,857
THEN CBD BY INTERFERING WITH THE

1088
00:44:14,857 --> 00:44:18,761
SIGNAL INDUCTION COULD MAKE A

1089
00:44:18,761 --> 00:44:20,196
BIGGER SODIUM CURRENT OR MORE

1090
00:44:20,196 --> 00:44:20,663
FIRING.

1091
00:44:20,663 --> 00:44:23,966
AND BY LOOKING AT THE COMPOUND

1092
00:44:23,966 --> 00:44:26,669
EBST, THAT A SYNTHESIZED

1093
00:44:26,669 --> 00:44:28,104
STIMULATOR OF NAV 1.1, THE

1094
00:44:28,104 --> 00:44:32,708
SODIUM CHANNEL THAT'S IN THE

1095
00:44:32,708 --> 00:44:34,577
ALBUT MIN NEURONS WAS ABLE TO

1096
00:44:34,577 --> 00:44:37,713
MIMIC THE EFFECTS OF CBD AND IN

1097
00:44:37,713 --> 00:44:40,016
FACT CONCLUDE THE EFFECTS OF CBD

1098
00:44:40,016 --> 00:44:44,887
AND THIS WAS MIRRORED BY ANOTHER

1099
00:44:44,887 --> 00:44:48,558
COMPOUND, AA43729, ONCE AGAIN

1100
00:44:48,558 --> 00:44:49,959
MIMICKING THE EFFECTS OF CBD.

1101
00:44:49,959 --> 00:44:52,495
SO WE THINK WE ARE ON TO WHAT

1102
00:44:52,495 --> 00:44:55,431
THE BASIC MECHANISM OF HOW CBD

1103
00:44:55,431 --> 00:44:57,066
MIGHT ACT AND WE THEN TRY TO

1104
00:44:57,066 --> 00:44:59,702
TEST WHAT THE TIMING OF THE

1105
00:44:59,702 --> 00:45:01,504
INPUT NEEDED TO BE BY DOING AN

1106
00:45:01,504 --> 00:45:05,575
OPTICAL IMAGES O GENETIC

1107
00:45:05,575 --> 00:45:06,309
EXPERIMENT EXPRESSING CHANNEL

1108
00:45:06,309 --> 00:45:08,544
ROUGH ATOM DOBSIN IN PV NEURONS

1109
00:45:08,544 --> 00:45:10,413
AND SHOWING WE CAN MIMIC THE

1110
00:45:10,413 --> 00:45:12,148
EFFECT OF CBD WITHOUT ANY DRUG

1111
00:45:12,148 --> 00:45:15,318
AT ALL BY SHINING LIGHT ON THE

1112
00:45:15,318 --> 00:45:19,989
TERMINALS OF THE PV NEURONS ON

1113
00:45:19,989 --> 00:45:21,958
TO THE CELLS AND YOU CAN SEE

1114
00:45:21,958 --> 00:45:24,493
REGARDLESS OF WHETHER YOU HAVE

1115
00:45:24,493 --> 00:45:26,662
WEAK STIMULATION, STRONG

1116
00:45:26,662 --> 00:45:27,930
STIMULATION, THE FEET FORWARD

1117
00:45:27,930 --> 00:45:29,332
INHIBITION MIMIC THE EFFECT OF

1118
00:45:29,332 --> 00:45:31,334
CBD, THIS IS NOT PRODUCED IF

1119
00:45:31,334 --> 00:45:36,038
WE'VE SHOWN A VERY GENERAL AND

1120
00:45:36,038 --> 00:45:37,607
TIME INDISCRIMINATE STUDY GLOW

1121
00:45:37,607 --> 00:45:39,809
OF LIGHT, THEN WE SAW THE EXACT

1122
00:45:39,809 --> 00:45:41,777
OPPOSITE OF THIS EFFECT.

1123
00:45:41,777 --> 00:45:44,080
AND SCOTT OWEN WHO IS WORKING

1124
00:45:44,080 --> 00:45:51,721
WITH THE INTRAMURAL DIRECTORS,

1125
00:45:51,721 --> 00:45:54,256
SON, RELATIVE, WAS THE 1 WHO

1126
00:45:54,256 --> 00:45:59,629
DESCRIBED THIS FOR PV NEURONS

1127
00:45:59,629 --> 00:46:01,130
USINGOXITOSEIN, THE GENERAL

1128
00:46:01,130 --> 00:46:02,598
LIGHT DOES WHATOXITOSEIN DOES,

1129
00:46:02,598 --> 00:46:04,166
SO WHAT YOU NEED IN ORDER TO

1130
00:46:04,166 --> 00:46:06,202
PREVENT THE THROUGH PUT OF

1131
00:46:06,202 --> 00:46:07,637
TRANSMISSION IS PRECISELY TIMED

1132
00:46:07,637 --> 00:46:09,271
ACTIVATION OF THE PV NEURONS,

1133
00:46:09,271 --> 00:46:11,140
THE RIGHT PLACE AND AT THE RIGHT

1134
00:46:11,140 --> 00:46:14,076
TIME, RIGHT AS YOU WOULD EXPECT

1135
00:46:14,076 --> 00:46:15,845
FROM FEET FORWARD INHIBITION, SO

1136
00:46:15,845 --> 00:46:18,814
THE CONCLUSION IS THAT CBD IS A

1137
00:46:18,814 --> 00:46:19,649
VERY CLEVER DRUG.

1138
00:46:19,649 --> 00:46:22,551
IT DAMPENS THE PROPAGATION OF

1139
00:46:22,551 --> 00:46:24,654
HIFREQUENCY ACTIVITY IN THE

1140
00:46:24,654 --> 00:46:27,289
HIPPOCAMPUS BY INCREASING PV

1141
00:46:27,289 --> 00:46:28,824
INTERNEURON FIRING AND

1142
00:46:28,824 --> 00:46:30,292
CONCOMITANTLY DECREASING THE

1143
00:46:30,292 --> 00:46:32,294
FIRING OF SST INTERNEURONS,

1144
00:46:32,294 --> 00:46:35,431
MAINTAINING SOME SORT OF PV SST,

1145
00:46:35,431 --> 00:46:37,299
I WANT TO USE THE WORD BALANCE,

1146
00:46:37,299 --> 00:46:38,834
DON'T WANT TO USE THE WORD

1147
00:46:38,834 --> 00:46:41,470
BALANCE BECAUSE IT REMINDS ME OF

1148
00:46:41,470 --> 00:46:45,007
EI BALANCE BUT ANYWAY, IT'S SOME

1149
00:46:45,007 --> 00:46:46,876
KIND OF HARMONY BETWEEN THE 2

1150
00:46:46,876 --> 00:46:47,843
TYPES OF INTERNEURONS, THE 1 YOU

1151
00:46:47,843 --> 00:46:49,412
NEED TO FIRE IS THE 1 THAT'S

1152
00:46:49,412 --> 00:46:53,649
MADE THE FIRE AND THAT DAMPENS

1153
00:46:53,649 --> 00:46:54,483
SPIKE TRANSMISSION BY PATHWAY

1154
00:46:54,483 --> 00:46:56,419
GIVES RAMETTAL CELLS AND THE SST

1155
00:46:56,419 --> 00:46:58,854
NEURONS ARE NOT ALLOWED TO

1156
00:46:58,854 --> 00:47:02,725
INHIBIT THE PV NEURONS O SO THAT

1157
00:47:02,725 --> 00:47:04,260
MAKES THE EFFECT EVEN STRONGER.

1158
00:47:04,260 --> 00:47:06,462
WE CAN MIMIC THE EFFECT BY

1159
00:47:06,462 --> 00:47:07,863
ACTIVATING SODIUM CHANNELS AND

1160
00:47:07,863 --> 00:47:10,032
THEY MIMIC AND INCLUDE CBD

1161
00:47:10,032 --> 00:47:10,666
CIRCUIT ACTION.

1162
00:47:10,666 --> 00:47:11,701
AND THE TIMING IS IMPORTANT

1163
00:47:11,701 --> 00:47:15,271
BECAUSE THAT'S WHEN YOU NEED THE

1164
00:47:15,271 --> 00:47:19,875
INHIBITORY INPUT TO PREVENT

1165
00:47:19,875 --> 00:47:21,577
FIRING AND THESE EXPERIMENTS

1166
00:47:21,577 --> 00:47:23,846
WHICH ARE DONE WITHOUT ADDED LPI

1167
00:47:23,846 --> 00:47:28,384
ARE BETTER SUITED TO THE

1168
00:47:28,384 --> 00:47:29,652
NEUROPSYCHIATRIC INDKAIGS THAT

1169
00:47:29,652 --> 00:47:31,087
CBD ARE USED FOR BECAUSE PEOPLE

1170
00:47:31,087 --> 00:47:34,724
WHO ARE TAKING CBD FOR WHATEVER

1171
00:47:34,724 --> 00:47:36,459
AILS THEM, SOMETIMES

1172
00:47:36,459 --> 00:47:37,827
INTELLIGENTLY AND SOMETIMES

1173
00:47:37,827 --> 00:47:40,062
BLINDLY, THEY'RE NOT EPILEPTIC

1174
00:47:40,062 --> 00:47:40,796
PATIENTS THEY'RE JUST PEOPLE

1175
00:47:40,796 --> 00:47:42,965
WORKING WITH THE BRAIN'S OWN

1176
00:47:42,965 --> 00:47:45,601
LEVEL OF LPI, SO THE VIRTUE OF

1177
00:47:45,601 --> 00:47:47,670
HAVING AN ENDOGENOUS SYSTEM IS

1178
00:47:47,670 --> 00:47:48,738
THAT IT'S MODULATING THE PROPERS

1179
00:47:48,738 --> 00:47:50,473
OF CIRCUIT AND REGULATING HOW

1180
00:47:50,473 --> 00:47:52,475
INFORMATION GETS TRAN FERRED AND

1181
00:47:52,475 --> 00:47:56,679
IT PROVIDES A STRATEGIC TARGET

1182
00:47:56,679 --> 00:47:57,246
FOR CBD ACTION.

1183
00:47:57,246 --> 00:47:59,448
NOW LET ME CHECK HOW I'M DOING

1184
00:47:59,448 --> 00:48:01,650
ON TIME, AND I'D LIKE TO SEGUE

1185
00:48:01,650 --> 00:48:04,286
TO THE LAST PART OF MY TALK AND

1186
00:48:04,286 --> 00:48:07,656
BELIEVE ME, THEY'RE NOT 50% MORE

1187
00:48:07,656 --> 00:48:09,391
SLIDES, THERE ARE ONLY MAYBE 33%

1188
00:48:09,391 --> 00:48:11,026
MORE SLIDES AND I THINK I HAVE

1189
00:48:11,026 --> 00:48:12,661
ENOUGH TIME TO DO THIS.

1190
00:48:12,661 --> 00:48:15,698
>> THIS MIGHT BE A GOOD
MOMENT,

1191
00:48:15,698 --> 00:48:16,732
I'M OVER HERE, THE OTHER

1192
00:48:16,732 --> 00:48:19,735
DIRECTION, I JUST WANT TO,A

1193
00:48:19,735 --> 00:48:20,503
NOUNS, YEAH, SORRY.

1194
00:48:20,503 --> 00:48:22,304
OUR SEND LIVE FEEDBACK BUTTON IS

1195
00:48:22,304 --> 00:48:24,073
NOT WORKING SO ANYONE WATCHING

1196
00:48:24,073 --> 00:48:25,508
IT REMOTELY AND THERE ARE A LOT

1197
00:48:25,508 --> 00:48:27,009
OF PEOPLE WATCHING REMOTELY,

1198
00:48:27,009 --> 00:48:37,520
SEND E-MAIL TO THE WAS OFFICE,

1199
00:48:38,487 --> 00:48:38,888
WALSOFFICE@OD.NIH.GOV.

1200
00:48:38,888 --> 00:48:39,922
>> THANK YOU, WE WANT ALL
THE

1201
00:48:39,922 --> 00:48:41,557
FEEDBACK WE CAN GET.

1202
00:48:41,557 --> 00:48:42,525
AND WE'RE HAPPY TO GET IT

1203
00:48:42,525 --> 00:48:44,426
WHETHER IT'S IN A CHAT OR E-MAIL

1204
00:48:44,426 --> 00:48:45,194
OR ANY FORM.

1205
00:48:45,194 --> 00:48:46,395
E-MAIL MIGHT BE EVEN BETTER

1206
00:48:46,395 --> 00:48:47,930
BECAUSE I CAN PASS IT ON TO MY

1207
00:48:47,930 --> 00:48:50,666
COLLEAGUES WHO ARE ALWAYS

1208
00:48:50,666 --> 00:48:51,967
ELECTRICKING FOR WAYS

1209
00:48:51,967 --> 00:48:53,302
TO--LOOKING FOR WAYS OF

1210
00:48:53,302 --> 00:48:54,069
IMPROVING OUR WORK.

1211
00:48:54,069 --> 00:48:56,806
SO I DRIEB THIS VICIOUS CYCLE,

1212
00:48:56,806 --> 00:48:58,340
THIS POSITIVE FEEDBACK WHERE

1213
00:48:58,340 --> 00:48:59,742
SOMETIMES THE LIGAND AND ALWAYS

1214
00:48:59,742 --> 00:49:02,578
THE RESUPPORTOR THAT TRIGGERS AN

1215
00:49:02,578 --> 00:49:04,313
INN CREASE IN EXCITATION AND

1216
00:49:04,313 --> 00:49:05,948
DISCIPLINARY CREASE IN

1217
00:49:05,948 --> 00:49:07,516
INHIBITION IS ENHANCED BY

1218
00:49:07,516 --> 00:49:08,584
HYPER-ACTIVITY, A POSITIVE

1219
00:49:08,584 --> 00:49:10,152
FEEDBACK LOOP THAT'S INTERRUPTED

1220
00:49:10,152 --> 00:49:12,721
BY CBD, THIS IS AT THE RECEPTOR,

1221
00:49:12,721 --> 00:49:15,724
SYNAPSE LEVEL AND THAT CIRCUIT

1222
00:49:15,724 --> 00:49:17,359
LEVEL, THE NUMBER OF SPIKES THAT

1223
00:49:17,359 --> 00:49:19,995
CAN GET THROUGH, IS ENHANCED BY

1224
00:49:19,995 --> 00:49:24,033
A GREAT ENHANCEMENT OF FEET

1225
00:49:24,033 --> 00:49:25,835
FORWARD INNOVATION, AND

1226
00:49:25,835 --> 00:49:27,236
CONCOMITANT FEET FORWARD AND

1227
00:49:27,236 --> 00:49:29,071
BACK INHIBITION, AND TOGETHER

1228
00:49:29,071 --> 00:49:32,408
THIS DECREASES THE NET EPSB, AND

1229
00:49:32,408 --> 00:49:33,409
DECREASED SPIKE THROUGH PUT.

1230
00:49:33,409 --> 00:49:35,077
SO BOTH AT THE SYNAPTIC LEVEL

1231
00:49:35,077 --> 00:49:37,847
AND AT THE CIRCUIT LEVEL AND

1232
00:49:37,847 --> 00:49:41,483
NEURONAL FIRING LEVEL, CBD IS A

1233
00:49:41,483 --> 00:49:45,387
VERY EFFECTIVE AGENT IN

1234
00:49:45,387 --> 00:49:47,289
MODIFYING IMPULSE TRAFFIC AND

1235
00:49:47,289 --> 00:49:48,057
INFLAMMATION FLOW THROUGH THE

1236
00:49:48,057 --> 00:49:48,290
BRAIN.

1237
00:49:48,290 --> 00:49:51,327
I WOULD LIKE TO CLOSE WITH

1238
00:49:51,327 --> 00:49:54,196
MEDICAL DETECTIVE STORY ABOUT

1239
00:49:54,196 --> 00:49:54,396
KIDS.

1240
00:49:54,396 --> 00:49:57,299
WHICH WAS HEAD LINED HERE IN

1241
00:49:57,299 --> 00:50:00,469
SCIENCE AS SEQUENCING MYSTERIOUS

1242
00:50:00,469 --> 00:50:02,571
CASES, YIELDS MUTATIONS LINKED

1243
00:50:02,571 --> 00:50:04,139
TO SEIZURES AND ARRHYTHMIAS, AND

1244
00:50:04,139 --> 00:50:07,176
THIS GOES BACK TO MICHELLE'S

1245
00:50:07,176 --> 00:50:08,410
VERY KIND AND INTRODUCTION ABOUT

1246
00:50:08,410 --> 00:50:10,679
THINGS THAT INTEREST US AND I

1247
00:50:10,679 --> 00:50:18,420
THINK SHOULD INTEREST PEOPLE AT

1248
00:50:18,420 --> 00:50:18,854
NIH.

1249
00:50:18,854 --> 00:50:22,691
SO WHAT IS SUDC, WELL, IT'S SIDS

1250
00:50:22,691 --> 00:50:25,127
IN OLDER KIDS, THE ONLY

1251
00:50:25,127 --> 00:50:26,262
DISTINCTION BETWEEN THESE 2

1252
00:50:26,262 --> 00:50:27,763
SYNDROMES IS WHETHER THE CHILD

1253
00:50:27,763 --> 00:50:29,798
IS LESS THAN 1 OR OVER 1 AND

1254
00:50:29,798 --> 00:50:32,434
MOST OF US WOULD BELIEVE THERE'S

1255
00:50:32,434 --> 00:50:34,803
NO WATERSHED AND MECHANISM THAT

1256
00:50:34,803 --> 00:50:39,708
STOPS AT 1 YEAR AND THEN

1257
00:50:39,708 --> 00:50:40,476
BEGENERATEDS AT 12 MONTHS.

1258
00:50:40,476 --> 00:50:43,045
IN FACT, IT'S CONTINUUM AND

1259
00:50:43,045 --> 00:50:47,783
GENETICS IS CONFIRMING THIS

1260
00:50:47,783 --> 00:50:48,117
IDEA.

1261
00:50:48,117 --> 00:50:49,385
ALLOWING FOR ITS PREVALENCE MAY

1262
00:50:49,385 --> 00:50:54,456
BE NOT AS LARGE AS SIDS BUT

1263
00:50:54,456 --> 00:50:56,358
STILL A SUBSTANTIAL SUBTRACTION

1264
00:50:56,358 --> 00:50:56,959
OF SIDS PATIENTS.

1265
00:50:56,959 --> 00:51:01,163
IN FACT THE RATIO COULD BE

1266
00:51:01,163 --> 00:51:02,298
SOMETHING LIKE 3 OR 4 TO 1.

1267
00:51:02,298 --> 00:51:05,634
THE NUMBER OF CASES IS LESS FOR

1268
00:51:05,634 --> 00:51:10,072
SUDC, BUT THE FUNDING THE RATIO

1269
00:51:10,072 --> 00:51:11,941
IS PRACTICALLY INFINITE AND THE

1270
00:51:11,941 --> 00:51:13,142
RATIO OF PUBLICATIONS IS ALSO

1271
00:51:13,142 --> 00:51:16,178
EXTREMELY HIGH.

1272
00:51:16,178 --> 00:51:17,813
SO IF YOU NOMPLALLIZE THINGS

1273
00:51:17,813 --> 00:51:20,082
ACCORDING TO THE NUMBER OF

1274
00:51:20,082 --> 00:51:23,686
PATIENTS, SUDC IS

1275
00:51:23,686 --> 00:51:24,086
UNDERREPRESENTED.

1276
00:51:24,086 --> 00:51:26,388
SO HOW DO WE APPROACH THIS,

1277
00:51:26,388 --> 00:51:29,758
WELL, SOMEONE WHO'S BOTH A

1278
00:51:29,758 --> 00:51:33,896
RESEARCHER, AND A MOM WHO

1279
00:51:33,896 --> 00:51:36,899
SUFFERED A TRAGEDY EARLY IN THE

1280
00:51:36,899 --> 00:51:41,003
FAMILY STARTED A CONSORTIUM

1281
00:51:41,003 --> 00:51:45,908
CALLED THE SUDC REEJ TREE ASK

1282
00:51:45,908 --> 00:51:47,409
RESEARCH COLLABORATIVE AND SHE

1283
00:51:47,409 --> 00:51:49,712
TEAMED UP WITH OUR RESEARCH

1284
00:51:49,712 --> 00:51:51,914
PATHOLOGIST AND THEY REVIEWED

1285
00:51:51,914 --> 00:51:53,482
THE KIDS DEATH, MADE AN ANALYSIS

1286
00:51:53,482 --> 00:51:57,019
AND MADE A CASE REPORT IN

1287
00:51:57,019 --> 00:51:57,987
CLINICAL JOURNALS TO USE THIS

1288
00:51:57,987 --> 00:51:59,621
INFORMATION TO IESHES DEPTIFY

1289
00:51:59,621 --> 00:52:00,389
AT-RISK INDIVIDUALS AND THEY

1290
00:52:00,389 --> 00:52:06,929
TEAMED UP WITH PEOPLE IN

1291
00:52:06,929 --> 00:52:08,430
PEDIATRICS WITH COLUMBIA IN THE

1292
00:52:08,430 --> 00:52:09,231
GENETIC BACKGROUND AND PEOPLE

1293
00:52:09,231 --> 00:52:11,767
OUT IN THE COMMUNITY AT THE MAYO

1294
00:52:11,767 --> 00:52:13,435
CLINIC WHO WERE INVOLVED IN

1295
00:52:13,435 --> 00:52:14,837
DOING THE DETECTIVE STORY ABOUT

1296
00:52:14,837 --> 00:52:17,539
FIGURING OUT WHAT GENETIC AND

1297
00:52:17,539 --> 00:52:18,707
ENVIRONMENTAL FACTORS TRIGGER

1298
00:52:18,707 --> 00:52:22,111
SUDC, AND THEY COLLECTED UP TO

1299
00:52:22,111 --> 00:52:24,913
130 FAMILY TRIOS WHERE THERE IS

1300
00:52:24,913 --> 00:52:27,316
A DECEASED CHILD, BOY OR GIRL,

1301
00:52:27,316 --> 00:52:30,419
PRETTY MUCH 50/50 AND WOPARENTS

1302
00:52:30,419 --> 00:52:32,488
WHO ARE WILLING IN THE WAKE OF

1303
00:52:32,488 --> 00:52:34,857
THE TRAGEDY TO GIVE BLOOD

1304
00:52:34,857 --> 00:52:36,825
SAMPLES AND WHERE THEIR BLOOD

1305
00:52:36,825 --> 00:52:38,794
SAMPLES BEING BE COMPARED WITH

1306
00:52:38,794 --> 00:52:39,495
THAT OF THE CHILD.

1307
00:52:39,495 --> 00:52:42,531
AND SO THAT'S CALLED TRADITIONAL

1308
00:52:42,531 --> 00:52:47,336
ANALYSIS OF TRIOS, MOM, DAD AND

1309
00:52:47,336 --> 00:52:50,973
SON OR DAUGHTER AND THE CODING

1310
00:52:50,973 --> 00:52:52,975
AXONS OF THE INDIVIDUALS ARE

1311
00:52:52,975 --> 00:52:55,978
COMPARED, AND SO THIS IS A

1312
00:52:55,978 --> 00:52:57,413
COLLECTION AND ALMOST ALL KIDS

1313
00:52:57,413 --> 00:53:00,682
DIED IN THEIR SLEEP, AND VERY

1314
00:53:00,682 --> 00:53:02,051
FEW WHO ARE AWAKE.

1315
00:53:02,051 --> 00:53:03,118
I WILL COME BACK TO WHAT

1316
00:53:03,118 --> 00:53:07,689
HAPPENED WHILE THEY WERE

1317
00:53:07,689 --> 00:53:08,123
SLEEPING LATER.

1318
00:53:08,123 --> 00:53:10,893
IN MOST OF THE CASES, MAYBE 40%,

1319
00:53:10,893 --> 00:53:13,762
THE KIDS HAD SOME SORT OF

1320
00:53:13,762 --> 00:53:14,930
SEIZURE HISTORY, FEB RILE

1321
00:53:14,930 --> 00:53:16,865
SEIZURE, SOME OTHER TYPE OF

1322
00:53:16,865 --> 00:53:17,933
SEIZURE, SO THAT IMMEDIATELY

1323
00:53:17,933 --> 00:53:19,635
MAKING YOU THINK ABOUT BRAIN

1324
00:53:19,635 --> 00:53:20,869
CIRCUITS, AND THIS WORK WAS PUB

1325
00:53:20,869 --> 00:53:24,073
LIBRARY FOUNDATIONED A COUPLE

1326
00:53:24,073 --> 00:53:25,641
YEARS AGO.

1327
00:53:25,641 --> 00:53:28,744
SO THE EXOHM SEQUENCING OF THESE

1328
00:53:28,744 --> 00:53:29,945
TRIOS LED TO TABLES LIKE THIS,

1329
00:53:29,945 --> 00:53:32,481
AND THIS IS JUST THE FRAGMENT OF

1330
00:53:32,481 --> 00:53:34,183
A LONG LIST OF TABLES WHERE THEY

1331
00:53:34,183 --> 00:53:37,019
WERE ABLE TO COME UP WITH

1332
00:53:37,019 --> 00:53:38,220
CANDIDATE MUTATIONS THAT MIGHT

1333
00:53:38,220 --> 00:53:43,325
CONTRIBUTE TO THE DISORDER.

1334
00:53:43,325 --> 00:53:46,161
AND SOMETIMES THEY WERE

1335
00:53:46,161 --> 00:53:47,229
FORTUITOUSLY FOUND MUTATIONS

1336
00:53:47,229 --> 00:53:49,098
THAT WERE ALREADY DRIEBED IN THE

1337
00:53:49,098 --> 00:53:50,732
DATABASE AS POTENTIALLY BEING

1338
00:53:50,732 --> 00:53:51,300
PATHOGENIC.

1339
00:53:51,300 --> 00:53:56,839
THIS IS A DESCRIPTION VARIED ON

1340
00:53:56,839 --> 00:53:58,407
PRODUCED BY A DATABASE AND THEY

1341
00:53:58,407 --> 00:54:00,442
HAVE NUMBERS, THEY HAVE VARIOUS

1342
00:54:00,442 --> 00:54:04,546
WAYS OF CATALOGING THEM, AND SO,

1343
00:54:04,546 --> 00:54:06,849
WE USE THIS AS A WAY OF

1344
00:54:06,849 --> 00:54:08,584
EDUCATING OURSELVES INTO HOW

1345
00:54:08,584 --> 00:54:09,518
GENETICISTS APPROACH THINGS

1346
00:54:09,518 --> 00:54:12,721
TAKING THIS AS A TEST CASE, A

1347
00:54:12,721 --> 00:54:14,456
TRAGIC TEST CASE BUT 1 THAT

1348
00:54:14,456 --> 00:54:16,191
OFFERED OPPORTUNITIES AND WE

1349
00:54:16,191 --> 00:54:22,030
COMPARED THE EFFECTS OF

1350
00:54:22,030 --> 00:54:23,365
SYNONYMOUS VARIANTS AND

1351
00:54:23,365 --> 00:54:24,333
NON-SYNONYMOUS VARIANTS.

1352
00:54:24,333 --> 00:54:26,034
VARIANTS THAT DID NOT CHANGE THE

1353
00:54:26,034 --> 00:54:29,438
AMINO ACID THAT WAS CODED FOR OR

1354
00:54:29,438 --> 00:54:30,572
NON-SYNONYMOUS VARIANTS THAT

1355
00:54:30,572 --> 00:54:32,174
COULD FEBRUARY EXAMPLE CHANGE A

1356
00:54:32,174 --> 00:54:37,513
DPLI SEEN TO A SERIES POINTSINE

1357
00:54:37,513 --> 00:54:40,582
AND MATT HALVERSON, A GREAT

1358
00:54:40,582 --> 00:54:42,317
GENERATEDETTIST, DID THE

1359
00:54:42,317 --> 00:54:43,685
ANALYSIS, THE SYNONYMOUS

1360
00:54:43,685 --> 00:54:44,887
VARIANTS PROVIDED GREAT CONTROL,

1361
00:54:44,887 --> 00:54:46,421
BECAUSE THERE'S BEEN A CHANGE IN

1362
00:54:46,421 --> 00:54:48,190
THE DNA BUT NO CHANGE IN THE

1363
00:54:48,190 --> 00:54:52,628
PROTEIN, WE'RE NOT EXPECTING

1364
00:54:52,628 --> 00:54:56,198
THESE TO BE LETHAL, IN FASTBALL

1365
00:54:56,198 --> 00:54:57,766
WE FOUND THAT THE SUBSET OF

1366
00:54:57,766 --> 00:55:02,604
YEENS WHICH ARE LABELED CARDIAC

1367
00:55:02,604 --> 00:55:03,972
EPILEPSY YEANS NOT

1368
00:55:03,972 --> 00:55:04,806
DISTINGUISHING BETWEEN

1369
00:55:04,806 --> 00:55:05,574
ELECTRICAL ACTIVITY, BETWEEN THE

1370
00:55:05,574 --> 00:55:07,943
HEART OR THE BRAIP, WE LUCHED

1371
00:55:07,943 --> 00:55:09,678
THEM ALTOGETHER AND WE HAD 137

1372
00:55:09,678 --> 00:55:11,547
YEENS AND WE LOOKED TO SEE WHAT

1373
00:55:11,547 --> 00:55:14,116
WERE THE ODDS THAT YOU WOULD

1374
00:55:14,116 --> 00:55:16,785
FIND A DE NOVO MUTATION IN THIS

1375
00:55:16,785 --> 00:55:20,289
SUBSET OF YEEN ANDS IN FACT, WE

1376
00:55:20,289 --> 00:55:24,793
FOUND THAT THE NON-SYNONYMOUS

1377
00:55:24,793 --> 00:55:27,029
VARIANTS WERE IN THESE

1378
00:55:27,029 --> 00:55:29,131
PARTICULAR GENES WERE

1379
00:55:29,131 --> 00:55:30,599
SIGNIFICANTLY AFFECTED BY

1380
00:55:30,599 --> 00:55:33,335
THE.WHERE ARE 032 LEVEL, SO

1381
00:55:33,335 --> 00:55:34,703
THESE YEENS ARE A NATURAL PLACE

1382
00:55:34,703 --> 00:55:37,105
TO LOOK BECAUSE THEY SHOW THE

1383
00:55:37,105 --> 00:55:39,007
SIGNS OF WHAT YOU EXPECT IF THEY

1384
00:55:39,007 --> 00:55:41,043
PRODUCE DISEASE, THE CONTROL OF

1385
00:55:41,043 --> 00:55:42,311
HAVING THE SYNONYMOUS VARIANCE

1386
00:55:42,311 --> 00:55:43,979
IS VERY SATISFYING BECAUSE THESE

1387
00:55:43,979 --> 00:55:45,447
WERE NOT SIGNIFICANTLY CHANGED

1388
00:55:45,447 --> 00:55:46,848
AND AS YOU WOULD EXPECT BECAUSE

1389
00:55:46,848 --> 00:55:51,820
THESE ARE NOT CHANGING THE

1390
00:55:51,820 --> 00:55:52,721
PROTEIN.

1391
00:55:52,721 --> 00:55:55,123
NOW LET'S TAKE THESE GENES, TAKE

1392
00:55:55,123 --> 00:55:56,858
THE MUTATION, WE FOUND IN THE

1393
00:55:56,858 --> 00:55:58,293
SUBSET OF 125 INDIVIDUALS ASK

1394
00:55:58,293 --> 00:56:03,966
RUN THESE AGAINST OTHER DECS OF

1395
00:56:03,966 --> 00:56:06,568
KIDS, CANCERS, NOT EXPECTING

1396
00:56:06,568 --> 00:56:08,770
ANYTHING, OTHER RARE DISEASES,

1397
00:56:08,770 --> 00:56:12,741
ASTHMA, DEVELOPMENTAL DELAY AND

1398
00:56:12,741 --> 00:56:15,377
ALL THESE PLACES, THERE WAS NO

1399
00:56:15,377 --> 00:56:17,212
ENRICHMENT OF THESE, THE GENES

1400
00:56:17,212 --> 00:56:21,383
IN THESE DISEASES, IN OUR

1401
00:56:21,383 --> 00:56:24,353
SUBSET, BUT IF WE LOOK AT AUTISM

1402
00:56:24,353 --> 00:56:25,921
WHERE THERE ARE 700?

1403
00:56:25,921 --> 00:56:28,023
SEVENTEEN GENES IMPLICATED BY

1404
00:56:28,023 --> 00:56:29,858
THE SIMONS FOUNDATION OR OTHER

1405
00:56:29,858 --> 00:56:31,159
ORGANIZATIONS, WE EXPECTED TO

1406
00:56:31,159 --> 00:56:33,428
SEE AN OVERLAP OF ABOUT 4 AND

1407
00:56:33,428 --> 00:56:35,497
HALF IN 4 AND HALF CASES BUT WE

1408
00:56:35,497 --> 00:56:43,672
SAW IN 11 CASES THERE WAS AN

1409
00:56:43,672 --> 00:56:47,042
OVERLAP AND AN ENRICHMENT WITH A

1410
00:56:47,042 --> 00:56:47,609
HIGHLY SIGNIFICANT P-VALUE

1411
00:56:47,609 --> 00:56:49,478
TELLING US THAT IN THE GENETIC

1412
00:56:49,478 --> 00:56:51,446
ALONE THAT THE DISEASES THAT

1413
00:56:51,446 --> 00:56:54,216
COME UP IN SUD ARE HIGHLY

1414
00:56:54,216 --> 00:56:55,050
RELEVANT AND VICE VERSA AND THIS

1415
00:56:55,050 --> 00:56:57,052
IS THE TYPE OF ANALYSIS YOU CAN

1416
00:56:57,052 --> 00:56:58,987
DO WHEN YOU'RE NOT ACTUALLY

1417
00:56:58,987 --> 00:57:02,224
LOOKING FOR SOMETHING, YOU DON'T

1418
00:57:02,224 --> 00:57:03,525
HAVE A PREDETERMINED HYPOTHESIS,

1419
00:57:03,525 --> 00:57:04,693
YOU'RE JUST TAKING WHAT IS GIVEN

1420
00:57:04,693 --> 00:57:09,064
TO YOU BY PEOPLE COMING INTO THE

1421
00:57:09,064 --> 00:57:09,331
REGISTRY.

1422
00:57:09,331 --> 00:57:11,500
SO THAT'S THE CONCLUSION AND

1423
00:57:11,500 --> 00:57:13,101
CONFIRMS WHAT MANY PEOPLE HAVE

1424
00:57:13,101 --> 00:57:16,171
ALWAYS BELIEVED THAT AUTISM AND

1425
00:57:16,171 --> 00:57:20,509
EPILEPSY HAVE A STRONG OVERLAP

1426
00:57:20,509 --> 00:57:23,412
EMPLOY NOT AUTISM AND HEART

1427
00:57:23,412 --> 00:57:26,248
DISEASE OR CARDIAC

1428
00:57:26,248 --> 00:57:27,749
ARITHMETRICSAS, AUTISM AND

1429
00:57:27,749 --> 00:57:28,417
EPILEPSY.

1430
00:57:28,417 --> 00:57:29,751
JOHN WANG TOOK A DIFFERENT

1431
00:57:29,751 --> 00:57:31,386
APPROACH, HE LOOKED AT THE

1432
00:57:31,386 --> 00:57:32,654
YEERNS THAT WERE CHARACTERIZED

1433
00:57:32,654 --> 00:57:35,223
AND PUT THEM INTO PROTEIN,

1434
00:57:35,223 --> 00:57:37,025
PROTEIN INTERACTION NET WORKS SO

1435
00:57:37,025 --> 00:57:39,127
PEOPLE CATALOG THE WAY PROTEINS

1436
00:57:39,127 --> 00:57:40,862
INTERACT WITH PARTNERS BY DOING

1437
00:57:40,862 --> 00:57:43,065
REAL HONEST TO GOODNESS

1438
00:57:43,065 --> 00:57:45,067
BIOCHEMISTRY AND THEY FIND THAT

1439
00:57:45,067 --> 00:57:49,905
THE GENES WE FIND AFFECTED BIKE

1440
00:57:49,905 --> 00:57:53,975
[INDISCERNIBLE] RYR2 AND 2 CASES

1441
00:57:53,975 --> 00:57:55,610
EACH AND CAL-MODUE LYNN WERE ALL

1442
00:57:55,610 --> 00:57:57,946
PART OF A SOCIAL NETWORK, A

1443
00:57:57,946 --> 00:57:59,781
NETWORK BETWEEN ENCODED PROTEINS

1444
00:57:59,781 --> 00:58:01,149
THAT PHYSICALLY IRPT ACT WITH

1445
00:58:01,149 --> 00:58:04,019
EACH OTHER AND FOR SYNONYMOUS

1446
00:58:04,019 --> 00:58:08,557
VARIANTS THIS ENRICHMENT VALUE

1447
00:58:08,557 --> 00:58:10,859
WAS PRACTICALLY A CHANCE WHEREAS

1448
00:58:10,859 --> 00:58:15,163
IN THE NON-SYNONYMOUS PROTEIN

1449
00:58:15,163 --> 00:58:16,631
VARIANTS, THE LIKELIHOOD OF

1450
00:58:16,631 --> 00:58:19,801
THERE BEING THIS MUCH

1451
00:58:19,801 --> 00:58:20,635
PROTEIN-PROTEIN INTERACTION IS

1452
00:58:20,635 --> 00:58:21,002
SIGNIFICANT.

1453
00:58:21,002 --> 00:58:23,972
SO NOT ONLY DO THE PROTEINS

1454
00:58:23,972 --> 00:58:25,507
CAUSE LETH AGALLITY BUT THEY

1455
00:58:25,507 --> 00:58:28,510
CAUSE IT IN PROTEIN, PROTEIN

1456
00:58:28,510 --> 00:58:29,077
ISHT WORKS.

1457
00:58:29,077 --> 00:58:31,747
THIS IS NOT ONLY TRUE OF A

1458
00:58:31,747 --> 00:58:33,515
CLUSTER, KNOWN FOR ITS ROLE IN

1459
00:58:33,515 --> 00:58:35,317
CALCIUM REGULATION, IT WAS ALSO

1460
00:58:35,317 --> 00:58:39,454
TRUE IN A CLUSTER KNOWN FOR

1461
00:58:39,454 --> 00:58:41,656
NEURAL DEVELOPMENT WHICH IS VERY

1462
00:58:41,656 --> 00:58:42,724
INTERESTING BECAUSE WE'RE NOT

1463
00:58:42,724 --> 00:58:44,326
EXPECTING THIS, WE WERE LOOKING

1464
00:58:44,326 --> 00:58:45,861
FOR SOMETHING THAT WOULD ACT

1465
00:58:45,861 --> 00:58:50,132
ACUTELY, THIS SAYS THAT SOME OF

1466
00:58:50,132 --> 00:58:51,299
THE GENES WE FOUND CLUSTERED

1467
00:58:51,299 --> 00:58:52,901
TOGETHER BECAUSE OF PROTEIN

1468
00:58:52,901 --> 00:58:54,970
INTERACS THAT WERE IMPORTANT IN

1469
00:58:54,970 --> 00:59:01,076
DEVELOPING THE NERVOUS SYSTEM.

1470
00:59:01,076 --> 00:59:02,778
SO SO THAT ARE THE EFFECTS OF

1471
00:59:02,778 --> 00:59:04,312
THESE GENES, SOME OF THEM WERE

1472
00:59:04,312 --> 00:59:09,851
ALREADY KNOWN, THE MUTATION AND

1473
00:59:09,851 --> 00:59:12,754
CAL-MODUE LYNN CAUSES SLOWER

1474
00:59:12,754 --> 00:59:16,091
CALCIUM ACTIVATION AND IS LETHAL

1475
00:59:16,091 --> 00:59:17,259
WITH BETA MINERGIC STIMULATION

1476
00:59:17,259 --> 00:59:19,194
IN MICE.

1477
00:59:19,194 --> 00:59:20,295
THE [INDISCERNIBLE] MUTATION,

1478
00:59:20,295 --> 00:59:22,931
CAUSED THE CHANGE IN THE CALCIUM

1479
00:59:22,931 --> 00:59:26,168
TRANSIENT AND A SLOWING OF THE

1480
00:59:26,168 --> 00:59:27,469
CALCIUM TRANSIT, I'M NOT SURE

1481
00:59:27,469 --> 00:59:30,205
WHAT WELL MEANS BUT THERE'S A

1482
00:59:30,205 --> 00:59:31,173
DEFINITE PHENOTYPE IN CALCIUM

1483
00:59:31,173 --> 00:59:33,275
RELEASE IN CELLS AND FINALLY, 1

1484
00:59:33,275 --> 00:59:34,943
OF THE OTHER MUTATIONS WE FOUND

1485
00:59:34,943 --> 00:59:38,113
IN OUR DATA SET, HAD BEEN

1486
00:59:38,113 --> 00:59:40,382
PREVIOUSLY IMPORTANT IN A

1487
00:59:40,382 --> 00:59:42,484
SYNDROMIC FORM OF AUTISM CALLED

1488
00:59:42,484 --> 00:59:43,985
TIMOTHY SYNDROME WHICH IS

1489
00:59:43,985 --> 00:59:46,521
CHARACTERIZED BY LONG HEART

1490
00:59:46,521 --> 00:59:49,391
BEATS AND TENDENCYS TO

1491
00:59:49,391 --> 00:59:49,691
ARRHYTHMIAS.

1492
00:59:49,691 --> 00:59:51,326
WE CHARACTERIZE OURSELVES AND

1493
00:59:51,326 --> 00:59:54,062
THIS IS GARY L. GRANT WITH THE

1494
00:59:54,062 --> 00:59:55,096
L-TYPE OF THE CALCIUM CURRENT

1495
00:59:55,096 --> 00:59:57,833
AND SHE FOUND THAT THERE FTION A

1496
00:59:57,833 --> 01:00:00,101
SIGNIFICANT PROLONGATION OF THE

1497
01:00:00,101 --> 01:00:01,903
TIME COURSE OF THE CURRENT IN

1498
01:00:01,903 --> 01:00:03,405
EITHER THE 2 MUTATIONS WHICH

1499
01:00:03,405 --> 01:00:04,706
APPEARED IN OUR DATA SET, THIS

1500
01:00:04,706 --> 01:00:12,747
IS A COMMON FEATURE OF COMMON

1501
01:00:12,747 --> 01:00:14,516
MUTATIONS THAT CAUSE ARRHYTHMIAS

1502
01:00:14,516 --> 01:00:17,552
AND CHANGES IN NERVOUS SYSTEM AS

1503
01:00:17,552 --> 01:00:18,086
WELL, HIGHLY SIGNIFICANT

1504
01:00:18,086 --> 01:00:19,154
INCREASE AND HOW MUCH THERE IS

1505
01:00:19,154 --> 01:00:21,490
LATE IN THE VOLTAGE AND

1506
01:00:21,490 --> 01:00:26,928
ACTIVATION IS GREATLY SLOWED BY

1507
01:00:26,928 --> 01:00:28,730
THE MUTATIONS.

1508
01:00:28,730 --> 01:00:31,466
SO PUTTING IT ALING IT, WE THINK

1509
01:00:31,466 --> 01:00:34,202
THAT LONGER CHANNELS CREATE

1510
01:00:34,202 --> 01:00:37,873
LONGER CALCIUM FLUX AND LONGER

1511
01:00:37,873 --> 01:00:39,841
CALCIUM FLUX CAUSES LATER

1512
01:00:39,841 --> 01:00:41,009
DEPOLARIZATIONS THAT ARE A

1513
01:00:41,009 --> 01:00:44,246
TEXTBOOK EXAMPLE OF HOW YOU CAN

1514
01:00:44,246 --> 01:00:45,680
PRODUCE LETHAL ARRHYTHMIAS AND

1515
01:00:45,680 --> 01:00:48,450
IT'S BOTH AMUSING AND SAD FOR ME

1516
01:00:48,450 --> 01:00:50,519
TO REALIZE I WORKED ON THIS PER

1517
01:00:50,519 --> 01:00:52,521
A BETTER PART OF 3 DECADES GOING

1518
01:00:52,521 --> 01:00:55,156
BACK TO MY WORK ON HEART TISSUE

1519
01:00:55,156 --> 01:00:59,995
THAT MICHELLE ANTWON ALLUDED TO.

1520
01:00:59,995 --> 01:01:04,666
MEAN WHILE A GROUP IN BUSTON'S

1521
01:01:04,666 --> 01:01:06,768
PUBLISHED SHORTLY AFTER WE DID,

1522
01:01:06,768 --> 01:01:07,369
INDEPENDENTLY, DIFFERENT DATA

1523
01:01:07,369 --> 01:01:08,770
SET OF PATIENTS AND CAME UP WITH

1524
01:01:08,770 --> 01:01:11,206
A VERY SIMILAR CONCLUSION THAT

1525
01:01:11,206 --> 01:01:15,644
ION CHANNELS AND OTHER PROTEINS

1526
01:01:15,644 --> 01:01:17,145
INVOLVED ARE INVOLVED AND

1527
01:01:17,145 --> 01:01:19,147
THEY--YOU COULD TAKE THE 2 DATA

1528
01:01:19,147 --> 01:01:21,449
SETS TOGETHER AND THEY WOULD BE

1529
01:01:21,449 --> 01:01:23,118
BOTH THE THEN OVERLAP AND THE

1530
01:01:23,118 --> 01:01:24,085
EXTENSION OF THE WORK AND

1531
01:01:24,085 --> 01:01:26,988
BECAUSE THIS IS A RELATIVELY

1532
01:01:26,988 --> 01:01:28,890
RARE DISEASE, IT'S AN EXAMPLE

1533
01:01:28,890 --> 01:01:29,858
WHERE SCIENTIFIC COOPERATION

1534
01:01:29,858 --> 01:01:33,295
COULD BE VERY FRUITFUL.

1535
01:01:33,295 --> 01:01:35,130
JUST BECAUSE HEART IS AN OBVIOUS

1536
01:01:35,130 --> 01:01:36,298
POSSIBILITY DOESN'T MEAN THE

1537
01:01:36,298 --> 01:01:38,233
BRAIN IS NOT INVOLVED BECAUSE

1538
01:01:38,233 --> 01:01:42,537
THE VERY SAME PROTEINS, ARE

1539
01:01:42,537 --> 01:01:45,173
THOUGHT TO BE INSTRUMENTAL IN

1540
01:01:45,173 --> 01:01:45,740
EXCITATION TRANSCRIPTION

1541
01:01:45,740 --> 01:01:49,044
COUPLING AND OTHER SIGNALING

1542
01:01:49,044 --> 01:01:51,379
ABNORMALITIES IN DIFFERENT CNS

1543
01:01:51,379 --> 01:01:52,480
DISORDERS LIKE SEIZURES,

1544
01:01:52,480 --> 01:01:55,517
MIGRAINE AND AUTISM, AND IN FACT

1545
01:01:55,517 --> 01:01:58,520
THE CALCIUM CHANNEL CONVEYS A

1546
01:01:58,520 --> 01:02:00,422
CONFIRMATIONAL SIGNAL THAT

1547
01:02:00,422 --> 01:02:01,623
DOESN'T NEED CALCIUM INFLUX JUST

1548
01:02:01,623 --> 01:02:05,660
BY THE PROTEIN CONFIRMATION THAT

1549
01:02:05,660 --> 01:02:06,928
COULD SIGNAL TO THE

1550
01:02:06,928 --> 01:02:08,463
[INDISCERNIBLE] RECEPTOR OR

1551
01:02:08,463 --> 01:02:11,399
OTHER PROTEINS LIKE KMK2 AND

1552
01:02:11,399 --> 01:02:14,603
THEREBY PRODUCE ABNORMAL

1553
01:02:14,603 --> 01:02:16,404
ELECTRICAL ACTIVITY.

1554
01:02:16,404 --> 01:02:18,807
SO THE JURY IS TILL OUT WHETHER

1555
01:02:18,807 --> 01:02:21,309
IT'S CARDIAC DISEASE OR NEURONAL

1556
01:02:21,309 --> 01:02:23,244
DEC OR BOTH, THE HEART DISEASE

1557
01:02:23,244 --> 01:02:26,348
COULD KILL YOU BECAUSE OF

1558
01:02:26,348 --> 01:02:28,149
ARRHYTHMIA, THE NEURONAL DISEASE

1559
01:02:28,149 --> 01:02:30,585
COULD CAUSE EPILEPSY CAN AN

1560
01:02:30,585 --> 01:02:34,789
EFFECT ON BREATHING AND LAURA

1561
01:02:34,789 --> 01:02:36,157
AND [INDISCERNIBLE] HAVE

1562
01:02:36,157 --> 01:02:37,759
PUBLISHED A PAPER IN NEUROLOGY

1563
01:02:37,759 --> 01:02:41,262
TAKING VIDEOS OF KIDS IN THEIR

1564
01:02:41,262 --> 01:02:43,898
BEDS RECORDED AS PART OF THE

1565
01:02:43,898 --> 01:02:45,600
NORMAL SURVEILLANCE THAT PARENTS

1566
01:02:45,600 --> 01:02:51,006
IMPOSE AND AFTER CAREFUL VIEWING

1567
01:02:51,006 --> 01:02:55,410
BY CLINICIANS, INDEPENDENT

1568
01:02:55,410 --> 01:02:56,344
REVIEWS, THEY CONCLUDED THAT

1569
01:02:56,344 --> 01:02:59,247
THERE WERE A SUBSTANTIAL NUMBER

1570
01:02:59,247 --> 01:03:00,682
THAT SHOWED TERMINAL

1571
01:03:00,682 --> 01:03:02,283
CONVULINGSS, EXTREMELY SAD FOR

1572
01:03:02,283 --> 01:03:04,219
THE FAMILIES BUT INFORMATIVE FOR

1573
01:03:04,219 --> 01:03:06,054
HOW WE CAN UNDERSTAND AND COPE

1574
01:03:06,054 --> 01:03:08,790
WITH THE DISEASE AND PREVENT AND

1575
01:03:08,790 --> 01:03:10,759
ULTIMATELY AND FIND A WAY OF

1576
01:03:10,759 --> 01:03:12,127
PREVENTING IT AND THESE ARE

1577
01:03:12,127 --> 01:03:14,829
PICTURES OF 3 OF THE KIDS WHOSE

1578
01:03:14,829 --> 01:03:16,665
ROTATIONS ARE ACTUALLY KNOWN.

1579
01:03:16,665 --> 01:03:18,633
THERE ARE ENOUGH OF MUTATIONS SO

1580
01:03:18,633 --> 01:03:19,934
THERE'S NO PROBLEM

1581
01:03:19,934 --> 01:03:21,036
CONFIDENTIALITY AND THESE

1582
01:03:21,036 --> 01:03:22,237
PICTURES WERE PROVIDED BY THE

1583
01:03:22,237 --> 01:03:24,973
FAMILIES AS PART OF THEIR FERVOR

1584
01:03:24,973 --> 01:03:27,308
TO TRY TO GAIN MORE PUBLIC

1585
01:03:27,308 --> 01:03:30,879
SUPPORT FOR THE IDEA OF STUDYING

1586
01:03:30,879 --> 01:03:39,320
THIS  STUDYING

1587
01:03:39,320 --> 01:03:39,854
THIS DEVASTATING DISORDER.

1588
01:03:39,854 --> 01:03:42,223
SO IN CONCLUSION, I WILL DO IT

1589
01:03:42,223 --> 01:03:44,259
IF 4 MINUTES, WE'VE BEEN

1590
01:03:44,259 --> 01:03:46,361
FOCUSING ON RARE VARIANTS WHO

1591
01:03:46,361 --> 01:03:48,063
HAVE AN EXTREME OR AUTOSOMAL

1592
01:03:48,063 --> 01:03:50,031
DOMAIN NABT EFFECT IN CAUSING A

1593
01:03:50,031 --> 01:03:52,567
FATALITY AND THESE HAVE HUGE

1594
01:03:52,567 --> 01:03:54,002
EFFECT SAYSS BUT OBVIOUSLY

1595
01:03:54,002 --> 01:03:55,437
THEY'RE VERY RARE IN THE GENERAL

1596
01:03:55,437 --> 01:03:55,770
POPULATION.

1597
01:03:55,770 --> 01:03:58,373
HOW ABOUT THE BIGGER PUBLIC

1598
01:03:58,373 --> 01:04:00,008
HEALTH PROBLEM OF OTHER VARIANTS

1599
01:04:00,008 --> 01:04:04,579
WHICH CAUSE OTHER DECS,

1600
01:04:04,579 --> 01:04:05,814
NEUROPSYCHIATRIC DECS

1601
01:04:05,814 --> 01:04:07,982
PRINCIPALLY WHICH ARE EXTREMELY

1602
01:04:07,982 --> 01:04:09,117
COMMON AFFECTING A LARGE NUMBER

1603
01:04:09,117 --> 01:04:11,286
OF PEOPLE BUT WHERE THE

1604
01:04:11,286 --> 01:04:13,955
INDIVIDUAL VARIATION CAUSES A

1605
01:04:13,955 --> 01:04:15,457
SMALL EFFECT.

1606
01:04:15,457 --> 01:04:16,758
AND I WILL SKIP THROUGH THIS AND

1607
01:04:16,758 --> 01:04:19,394
SAY, WE KNOW A LOT ABOUT THE

1608
01:04:19,394 --> 01:04:21,463
ETIOLOGY OF THESE RARE

1609
01:04:21,463 --> 01:04:24,933
MUTATIONS, HOW CAN WE STUDY THE

1610
01:04:24,933 --> 01:04:27,368
POORLY UNDERSTOOD 1S AND 10 IS

1611
01:04:27,368 --> 01:04:29,537
WE TEAM UP WITH IMENET CYSTS WHO

1612
01:04:29,537 --> 01:04:32,640
TELL US IN AN UNBIASED WAY THAT

1613
01:04:32,640 --> 01:04:36,177
THERE'S A STRONG ASSOCIATION

1614
01:04:36,177 --> 01:04:38,346
WITH THE CACNA1C GENE, THE VERY

1615
01:04:38,346 --> 01:04:41,049
GENE THAT CAUSES AUTISM, OR

1616
01:04:41,049 --> 01:04:42,884
CAUSES SUDC, THAT YEEN IS ALSO

1617
01:04:42,884 --> 01:04:45,086
IMPORTANT IN OTHER DISEASES THAT

1618
01:04:45,086 --> 01:04:52,594
AFFECT MILLIONS POOF INCLUDING

1619
01:04:52,594 --> 01:04:53,695
BIPOLAR DISORDER AND WHERE IT'S

1620
01:04:53,695 --> 01:04:55,663
SECOND IN GETTING TO THE TOP OF

1621
01:04:55,663 --> 01:04:56,131
THE CHARTS.

1622
01:04:56,131 --> 01:04:57,532
THE SAME LOCUST HAS BEEN

1623
01:04:57,532 --> 01:04:59,834
ASSOCIATED WITH MAJOR

1624
01:04:59,834 --> 01:05:01,402
DEPRESSION, ADD, AND ASD, SO

1625
01:05:01,402 --> 01:05:03,037
THIS SEEMS THIS IMPORTANT

1626
01:05:03,037 --> 01:05:04,539
PROTEIN IS NOT ONLY IMPORTANT

1627
01:05:04,539 --> 01:05:05,540
FOR NORMAL FUNCTION BUT IT'S

1628
01:05:05,540 --> 01:05:07,675
IMPORTANT FOR DISEASE AS WELL.

1629
01:05:07,675 --> 01:05:14,949
TO BE VERY BRIEF, THE GENOME IS

1630
01:05:14,949 --> 01:05:18,186
MOSTLY NONCODING DNA, THE DNA IS

1631
01:05:18,186 --> 01:05:20,155
ASSEMBLED BY SPLICING WHICH PUTS

1632
01:05:20,155 --> 01:05:21,422
TOGETHER MATURE TRANSCRIPT WHICH

1633
01:05:21,422 --> 01:05:23,925
GOES OUT OF THE CYTOPLASM AND IS

1634
01:05:23,925 --> 01:05:29,030
USED TO ENCODE PROTEIN, HOWEVER,

1635
01:05:29,030 --> 01:05:30,532
THAT--THOSE INSTRUCTIONS ONLY

1636
01:05:30,532 --> 01:05:33,835
USE ABOUT 1% OF THE REAL ESTATE

1637
01:05:33,835 --> 01:05:34,536
IN OUR GENOMES.

1638
01:05:34,536 --> 01:05:39,073
ONE% OF OUR GENOMES ARE ACTUALLY

1639
01:05:39,073 --> 01:05:41,009
ENCODING GIVING SPECIFIC

1640
01:05:41,009 --> 01:05:43,178
INSTRUCTIONS TO MAKE THE AMINO

1641
01:05:43,178 --> 01:05:44,512
ACID SEQUENCE IN THE PROTEIN,

1642
01:05:44,512 --> 01:05:48,016
THE REST OF THE GENOME IS

1643
01:05:48,016 --> 01:05:49,884
NONCODING, WHAT'S IT THERE FOR?

1644
01:05:49,884 --> 01:05:51,619
TO REGULATE THE ENCODING PARTS

1645
01:05:51,619 --> 01:05:54,389
EITHER BY MAKING THE CHROMATIN

1646
01:05:54,389 --> 01:05:56,825
INACCESSIBLE OR ACCESSIBLE OR

1647
01:05:56,825 --> 01:05:57,725
ALLOWING VARIOUS TRANSCRIPTION

1648
01:05:57,725 --> 01:05:59,794
FACTORS TO BIND AND TO SKIP THE

1649
01:05:59,794 --> 01:06:05,733
TO THE VERY END, WE ARE FOCUSING

1650
01:06:05,733 --> 01:06:07,669
ON CACNA1C ISSUE BECAUSE ABOUT

1651
01:06:07,669 --> 01:06:10,905
HALF THE GENE IS MADE UP OF 1

1652
01:06:10,905 --> 01:06:13,875
ENTRON AND THAT HARBARS THE

1653
01:06:13,875 --> 01:06:16,978
SNPs ARE IF SITS FRENNIA AND

1654
01:06:16,978 --> 01:06:18,012
OTHER MAJOR PSYCHIATRIC DISEASES

1655
01:06:18,012 --> 01:06:21,015
AND EVEN IF YOU NARROW IT DOWN

1656
01:06:21,015 --> 01:06:22,283
TO BASIAN ANALYSIS THAT ARE

1657
01:06:22,283 --> 01:06:24,586
THOUGHT TO BE CAUSAL, YOU STILL

1658
01:06:24,586 --> 01:06:25,453
HAVE SEVERAL INDIVIDUAL

1659
01:06:25,453 --> 01:06:26,721
VARIATIONS BUT WE'RE TAKING AN

1660
01:06:26,721 --> 01:06:31,359
APPROACH TO THIS LED BY INTREPID

1661
01:06:31,359 --> 01:06:33,261
COLLABORATOR NAMED SEAN WANG AND

1662
01:06:33,261 --> 01:06:36,598
WE'RE TRYING TO MAKE ARTIFICIAL

1663
01:06:36,598 --> 01:06:38,566
ALLELES WHICH CONTAIN ALL RISK

1664
01:06:38,566 --> 01:06:40,268
OR ALL PROTECTIVE VARIANTS OF

1665
01:06:40,268 --> 01:06:42,370
THIS DOING IT BY CLEVER

1666
01:06:42,370 --> 01:06:43,771
LEVERAGING OF BIOLOGICAL

1667
01:06:43,771 --> 01:06:44,072
TECHNIQUES.

1668
01:06:44,072 --> 01:06:45,974
WE HOPE TO PUT THESE INTO HUMAN

1669
01:06:45,974 --> 01:06:47,742
CELLS TO STUDY ORGANOID ANDS PUT

1670
01:06:47,742 --> 01:06:50,745
THEM INTO MICE, TO STUDY

1671
01:06:50,745 --> 01:06:52,247
BEHAVIOR AND HOPEFULLY THEN WE

1672
01:06:52,247 --> 01:06:54,482
WILL BE ABLE TO USE THE SAME

1673
01:06:54,482 --> 01:06:55,884
TYPE OF APPROACHES WE'VE USED

1674
01:06:55,884 --> 01:06:57,585
FOR MANYIERS TO ANALYZE THE

1675
01:06:57,585 --> 01:07:00,521
BASIS OF THE DEC, BY LITERALLY

1676
01:07:00,521 --> 01:07:06,361
COMPARING WHAT HAPPENS WHEN YOU

1677
01:07:06,361 --> 01:07:08,897
HAVE A LAYER THAT KEEPS YOU

1678
01:07:08,897 --> 01:07:10,665
PERFECTLY PROTECTED TO

1679
01:07:10,665 --> 01:07:11,833
SCHIZOPHRENIA, OR PERFECTLY

1680
01:07:11,833 --> 01:07:12,834
SUSCEPTIBLE TO IT.

1681
01:07:12,834 --> 01:07:14,369
WE'RE NOT EXPECTING ALL THE RISK

1682
01:07:14,369 --> 01:07:16,437
FACTORS TO ADD BECAUSE SOME OF

1683
01:07:16,437 --> 01:07:18,072
THEM ARE LINKED TO EACH OTHER

1684
01:07:18,072 --> 01:07:20,708
BUT WE EXPECT CUMULATIVELY YOU

1685
01:07:20,708 --> 01:07:22,010
SHOULD HAVE AN EFFECT THAT YOU

1686
01:07:22,010 --> 01:07:24,812
SHOULD BE ABLE TO SEE BEHAVIOR

1687
01:07:24,812 --> 01:07:27,548
CHANGE IN A MOUSE MODEL OR

1688
01:07:27,548 --> 01:07:29,484
EXPRESS EFFECT IN A HUMAN

1689
01:07:29,484 --> 01:07:31,252
DERIVED CELL.

1690
01:07:31,252 --> 01:07:33,621
SO TO CONCLUDE, NEURONS PROVIDE

1691
01:07:33,621 --> 01:07:35,523
CONNECTION AND FUNCTION AND SUDC

1692
01:07:35,523 --> 01:07:37,892
IS A CLEAR EXAMPLE OF THAT.

1693
01:07:37,892 --> 01:07:41,796
WE HAD NO IDEA WHERE TO LOOK,

1694
01:07:41,796 --> 01:07:43,698
GENIX TOLD US WHERE TO LOOK BUT

1695
01:07:43,698 --> 01:07:46,267
WHEN WE LOOK WE FIND THAT THE

1696
01:07:46,267 --> 01:07:48,169
FUNCTION APPROACHING THESE IS

1697
01:07:48,169 --> 01:07:49,704
DRASTICALLY AFFECTED.

1698
01:07:49,704 --> 01:07:50,305
THIS FUNCTION DIFS PERSPECTIVE

1699
01:07:50,305 --> 01:07:52,106
ON THE HEALTHY BRAIN, EVEN IN

1700
01:07:52,106 --> 01:07:54,542
THE HEALTHY BRAIN, THERE'S LPI,

1701
01:07:54,542 --> 01:07:55,944
IT'S BEING MADE ALL THE TIME AS

1702
01:07:55,944 --> 01:08:00,248
A RESULT OF THE ACTION OF PLA 2

1703
01:08:00,248 --> 01:08:02,917
AND NLP A IT1 AND IT'S FORTUNATE

1704
01:08:02,917 --> 01:08:05,253
SETTING IN EI RAT WROA EVEN

1705
01:08:05,253 --> 01:08:06,955
UNDER BASAL CONDITIONS SO WHEN

1706
01:08:06,955 --> 01:08:08,790
PEOPLE TALK ABOUT EI BALANCE

1707
01:08:08,790 --> 01:08:11,092
WHICH IS 1 POINT ALONG AN EI

1708
01:08:11,092 --> 01:08:13,761
RATIO CURVE AND RATIO ACCESS,

1709
01:08:13,761 --> 01:08:16,197
THAT'S AFFECTED BY LPI, WHO

1710
01:08:16,197 --> 01:08:18,633
CONTROLS THE CONTROLLERS, LIKE,

1711
01:08:18,633 --> 01:08:21,436
THE EXCITATORY AND INHIBITORY

1712
01:08:21,436 --> 01:08:22,737
SYNAPSES, CALCIUM CHANNELS, GENE

1713
01:08:22,737 --> 01:08:25,039
EXPRESSION STUDIES CAN FOCUS ON

1714
01:08:25,039 --> 01:08:27,208
THE SIGNALING PROTEINS THAT LIE

1715
01:08:27,208 --> 01:08:29,444
UP STREAM OF THOSE SIGNALING

1716
01:08:29,444 --> 01:08:33,081
PROTEINS, PROTEINS LIKE GPR 55.

1717
01:08:33,081 --> 01:08:36,617
THE LPI GPR 55 SYSTEM FOLLOWS

1718
01:08:36,617 --> 01:08:38,786
THE PRECEDENT OF ENDOKACCT

1719
01:08:38,786 --> 01:08:40,655
NABBOIDS AND THEIR RECEPTOR EC1

1720
01:08:40,655 --> 01:08:43,057
STUDIED HERE AT NIH AMONG MANY

1721
01:08:43,057 --> 01:08:44,792
OTHER PLACES AND DESPITE ALL

1722
01:08:44,792 --> 01:08:47,195
THIS INTENSE EFFORT, THE LIPID

1723
01:08:47,195 --> 01:08:48,596
SIGNALING STILL HOLDS MANY

1724
01:08:48,596 --> 01:08:49,897
MYSTERIES, BECAUSE THE LIPID IS

1725
01:08:49,897 --> 01:08:53,434
NOT AS EASY TO STUDY AS A

1726
01:08:53,434 --> 01:08:55,403
NEUROTRANSMITTER POLARIZED KIEWL

1727
01:08:55,403 --> 01:08:57,238
WHICH IS EASILY--MOLECULE WHICH

1728
01:08:57,238 --> 01:08:59,741
IS EASILY SOLUBLE AND BOLGTED

1729
01:08:59,741 --> 01:09:03,077
AND MADE INTO A AN EASILY PUT

1730
01:09:03,077 --> 01:09:04,879
INTO SOLUTION, THE LIPID DOESN'T

1731
01:09:04,879 --> 01:09:06,347
LIKE TO BE IN SOLUTION, IT LIKES

1732
01:09:06,347 --> 01:09:09,117
TO BE IN A MEMBRANE SO HOW DOES

1733
01:09:09,117 --> 01:09:10,852
IT GET RELEASED AND WHO RELEASES

1734
01:09:10,852 --> 01:09:12,487
IT AND HOW MUCH IS THERE AND HOW

1735
01:09:12,487 --> 01:09:14,722
IS IT TAKEN UP?

1736
01:09:14,722 --> 01:09:16,124
INHIBITORY NEURONS ARE ALSO

1737
01:09:16,124 --> 01:09:17,625
CONTROLLED BY FAST INHIBITION,

1738
01:09:17,625 --> 01:09:21,129
THAT'S ANOTHER 1 OF SIGNIFY HAD

1739
01:09:21,129 --> 01:09:23,031
MONITOR CHAMBER LAN'S LOVES, I

1740
01:09:23,031 --> 01:09:24,232
DIDN'T COVER THAT TODAY FOR THE

1741
01:09:24,232 --> 01:09:26,034
SAKE OF TIME.

1742
01:09:26,034 --> 01:09:28,169
THERE'S A CONVERGENCE BETWEEN

1743
01:09:28,169 --> 01:09:34,108
THE GENETICS LPIT, AND THE

1744
01:09:34,108 --> 01:09:37,011
PHARMACOLOGY OF CANNABINODIs,

1745
01:09:37,011 --> 01:09:39,947
BUT ACTUALLY CBD CAME ABOUT

1746
01:09:39,947 --> 01:09:47,488
BECAUSE A CHILD HARLOT HAD AND

1747
01:09:47,488 --> 01:09:49,357
THE PARENTS MOVED TO COLORADO TO

1748
01:09:49,357 --> 01:09:51,059
LOOK INTO THIS AND THAT'S WHAT

1749
01:09:51,059 --> 01:09:53,294
SET THE FIRE AND THAT'S WHAT LED

1750
01:09:53,294 --> 01:09:55,129
THE FDA TO LOOK INTO THIS AND

1751
01:09:55,129 --> 01:09:56,898
FOR THEM TO RUN THE UNBIASED

1752
01:09:56,898 --> 01:09:59,567
TRIALS AND WHICH IS BETTER THAN

1753
01:09:59,567 --> 01:10:00,835
TOTAL RESULTS, YOU NEED A LARGE

1754
01:10:00,835 --> 01:10:03,004
NUMBER OF PATIENT ANDS YOU NEED

1755
01:10:03,004 --> 01:10:04,906
TO MAKE IT SOUND FOR THE FDA

1756
01:10:04,906 --> 01:10:06,207
APPROVAL BUT THEY MANAGED TO GET

1757
01:10:06,207 --> 01:10:09,143
ALL THE WAY FROM 1 PATIENT AND 1

1758
01:10:09,143 --> 01:10:10,778
BRAVE FAMILY, ALL THE WAY TO A

1759
01:10:10,778 --> 01:10:10,978
DRUG.

1760
01:10:10,978 --> 01:10:13,081
AND FINALLY THE IMPORTANCE OF

1761
01:10:13,081 --> 01:10:16,751
NONCODING REGIONS, THIS IS THE

1762
01:10:16,751 --> 01:10:17,685
FRONTIER OF NEUROSCIENCE AS WELL

1763
01:10:17,685 --> 01:10:20,088
AS MANY OTHER FIELDS AND IT

1764
01:10:20,088 --> 01:10:22,356
BEHOOVES US TO FIND WAYS OF

1765
01:10:22,356 --> 01:10:23,591
TEAMING UP TOGETHER AND STUDYING

1766
01:10:23,591 --> 01:10:25,259
THE REGULATION OF THE REGULATORS

1767
01:10:25,259 --> 01:10:27,562
BY THE NONCODING REGIONS.

1768
01:10:27,562 --> 01:10:28,896
I WOULD LIKE TO THANK YOU VERY

1769
01:10:28,896 --> 01:10:30,398
MUCH FOR YOUR ATTENTION.

1770
01:10:30,398 --> 01:10:33,634
IT'S A LITTLE STRANGE TO BE HERE

1771
01:10:33,634 --> 01:10:35,470
AT THE HEART OF SCIENCE IN THE

1772
01:10:35,470 --> 01:10:37,738
U.S. AT LEAST AMONG PEOPLE WHO

1773
01:10:37,738 --> 01:10:38,840
ARE DOING SUCH GREAT WORK, I

1774
01:10:38,840 --> 01:10:42,276
HAVE A LOT OF RESPECT FOR THE

1775
01:10:42,276 --> 01:10:45,813
PIONEERING STUDIES OF PEOPLE

1776
01:10:45,813 --> 01:10:50,118
STUDYING INTERNEURONS, STUDYING

1777
01:10:50,118 --> 01:10:51,052
CANNABINOID RECEPTORS, STUDYING

1778
01:10:51,052 --> 01:10:52,753
SIGNALING IN MANY FORMS,

1779
01:10:52,753 --> 01:10:54,388
STUDYING HOW THE BRAIN WORKS AND

1780
01:10:54,388 --> 01:10:55,256
IT'S A PLEASURE FOR ME TO BE

1781
01:10:55,256 --> 01:10:57,125
HERE AND TALK TO YOU TODAY.

1782
01:10:57,125 --> 01:10:57,959
THANK YOU. 

1783
01:10:57,959 --> 01:11:03,865
KD--SALLY ASH PLAWZ

1784
01:11:03,865 --> 01:11:03,998
 

1785
01:11:03,998 --> 01:11:04,432
[ APPLAUSE ]

1786
01:11:04,432 --> 01:11:06,200
>> I LITTLE PAST THE HOUR
BUT I

1787
01:11:06,200 --> 01:11:09,904
WELCOME A QUESTION FROM THE

1788
01:11:09,904 --> 01:11:11,873
AUDIENCE. 

1789
01:11:11,873 --> 01:11:12,173
DR. RAWLING.

1790
01:11:12,173 --> 01:11:15,276
>> HI, HAVE YOU LOOKED AT
THE

1791
01:11:15,276 --> 01:11:18,112
HIGH LEVELS OF FEIGN

1792
01:11:18,112 --> 01:11:25,119
ILLEGALSALLA 9OT GPR55 CIRCUIT.

1793
01:11:25,119 --> 01:11:26,087
>> NO, WE HAVEN'T.

1794
01:11:26,087 --> 01:11:27,922
>> IF YOU HAVE AN E-MAIL
MEAS

1795
01:11:27,922 --> 01:11:29,790
SEND ME--

1796
01:11:29,790 --> 01:11:31,159
>> NO, IT'S JUST A
PERSONAL

1797
01:11:31,159 --> 01:11:33,995
OBSERVATION FOR SOMEONE WHO USED

1798
01:11:33,995 --> 01:11:36,797
TO HAVE FEIGN ILLEGALS ALANINE

1799
01:11:36,797 --> 01:11:38,266
INDUCED SEIZURES.

1800
01:11:38,266 --> 01:11:38,566
>> REALLY?

1801
01:11:38,566 --> 01:11:39,901
, NOT SOMETHING I WOULD HAVE

1802
01:11:39,901 --> 01:11:41,669
EXPECTED BUT THANK YOU FOR THAT

1803
01:11:41,669 --> 01:11:41,969
INFORMATION.

1804
01:11:41,969 --> 01:11:45,973
>> IN YOUR MODEL CIRCUIT,
IT

1805
01:11:45,973 --> 01:11:48,509
ONLY HAD POSITIVE FEEDBACK, SO,

1806
01:11:48,509 --> 01:11:51,812
IN THE LPI CIRCUIT, NOT EVERY

1807
01:11:51,812 --> 01:11:52,914
HIPPOCAMPUS IS PRONE TO

1808
01:11:52,914 --> 01:11:54,415
SEIZURES, SO WHAT DO YOU THINK

1809
01:11:54,415 --> 01:12:01,556
HAPPENS IN THE HEALTHY BRAIN TO

1810
01:12:01,556 --> 01:12:07,295
TASM DOWN OTHER ENDOCANNABINODS

1811
01:12:07,295 --> 01:12:10,531
IN THE SYSTEM?

1812
01:12:10,531 --> 01:12:13,201
>> THERE'S LPA, LIAISONS O

1813
01:12:13,201 --> 01:12:14,936
POSFETAL ACID SO IT HAS A

1814
01:12:14,936 --> 01:12:18,539
PHOSPHATE GROUP WHERE THE SUGAR

1815
01:12:18,539 --> 01:12:22,977
RING IS, SO IT'S LIAISONS O

1816
01:12:22,977 --> 01:12:29,183
PHOSPHO TITLE ASIT OLDER PEOPLE,

1817
01:12:29,183 --> 01:12:36,824
WITHOUT THE ACITOL, AND REMINDS

1818
01:12:36,824 --> 01:12:39,293
ME OF ROBERT DENEUROLOGIST O

1819
01:12:39,293 --> 01:12:41,162
ORDERING THE CHICKEN SALAD AND

1820
01:12:41,162 --> 01:12:42,530
TELLING THEM TO HOLD EVERYTHING

1821
01:12:42,530 --> 01:12:43,497
SO HE BEING GET TOAST.

1822
01:12:43,497 --> 01:12:46,500
SO IF YOU HAVE THE MIX OF LPA

1823
01:12:46,500 --> 01:12:48,135
AND LPI, YOU COULD HAVE A SYSTEM

1824
01:12:48,135 --> 01:12:49,003
TO DIAL YOU UP ANYWHERE YOU WANT

1825
01:12:49,003 --> 01:12:50,972
TO BE IN THE COORDINATES, IT'S

1826
01:12:50,972 --> 01:12:53,140
LIKE MY GOING TO WORK BY GOING

1827
01:12:53,140 --> 01:12:55,042
EAST AND NORTH OR GOING NORTH

1828
01:12:55,042 --> 01:12:55,776
AND THEN EAST.

1829
01:12:55,776 --> 01:12:58,679
SO THOSE 2 SYSTEMS ARE THE BEAR

1830
01:12:58,679 --> 01:13:00,815
MINIMUM THAT'S NEEDED IN ORDER

1831
01:13:00,815 --> 01:13:03,284
TO FOR LIPIDS TO DIAL UP

1832
01:13:03,284 --> 01:13:04,785
WHATEVER STRENGTH OF E AND I,

1833
01:13:04,785 --> 01:13:05,653
YOU WANT.

1834
01:13:05,653 --> 01:13:08,956
NOW LPA IS KNOWN TO DOWN

1835
01:13:08,956 --> 01:13:10,891
REGULATE BOTH EXCITATORY AND

1836
01:13:10,891 --> 01:13:11,892
INHIBITORY TRANSMISSION, BUT IT

1837
01:13:11,892 --> 01:13:14,662
HASN'T BEEN STUDIED IN THE SAME

1838
01:13:14,662 --> 01:13:16,297
TEDIOUS WAY WE DID IT TO FIGURE

1839
01:13:16,297 --> 01:13:18,599
OUT WHAT MAKE ITS REAL RELEASE

1840
01:13:18,599 --> 01:13:20,101
AND HOW STRONG IS IT AND IS IT

1841
01:13:20,101 --> 01:13:22,637
PART OF A FEEDBACK LOOP, BUT

1842
01:13:22,637 --> 01:13:24,238
THAT'S THE NEGATIVE COMPONENT,

1843
01:13:24,238 --> 01:13:28,743
SO LPI IS THERE, TO MAKE THE

1844
01:13:28,743 --> 01:13:29,543
HIPPOCAMPUS LIVE DANGEROUSLY,

1845
01:13:29,543 --> 01:13:31,879
LIVE NEAR THE EDGE, YOU KNOW PUT

1846
01:13:31,879 --> 01:13:33,481
YOUR BLIND FOLD ON, PUT YOUR

1847
01:13:33,481 --> 01:13:35,383
FOOT ON THE ACCELERATOR, TAKE

1848
01:13:35,383 --> 01:13:37,351
OFF THE BRAKES BUT THERE HAS TO

1849
01:13:37,351 --> 01:13:38,753
BE A COUNTERACTING TO THAT AND I

1850
01:13:38,753 --> 01:13:41,289
THINK IT COULD BE LPA OR IT

1851
01:13:41,289 --> 01:13:44,859
COULD BE AN ENDOGENOUS

1852
01:13:44,859 --> 01:13:46,427
CANNABINOID ANDACKING IN THE WAY

1853
01:13:46,427 --> 01:13:48,429
YOU'RE ALLUDING TO SO THE

1854
01:13:48,429 --> 01:13:50,164
COMBINATION OF HOW THESE WORK

1855
01:13:50,164 --> 01:13:52,466
TOGETHER IS UNCHARTED TERRITORY.

1856
01:13:52,466 --> 01:13:53,534
THANKS FOR THE QUESTION.

1857
01:13:53,534 --> 01:13:54,702
IN, THANK YOU EVERYONE FOR

1858
01:13:54,702 --> 01:13:57,838
COMING AND PLEASE JOIN US FOR

1859
01:13:57,838 --> 01:14:00,374
THE RECEPTION IN THE HALL, IN

1860
01:14:00,374 --> 01:14:01,342
THE LOBBY.

1861
01:14:01,342 --> 01:14:03,744
GOODBYE. 

1862
01:14:03,744 --> 01:14:04,045
THANK YOU.

1863
01:14:04,045 --> 01:14:14,255
[ APPLAUSE ]