>>> GOOD AFTERNOON, EVERYBODY. I THINK WE CAN GET STARTED. I'M THE DIRECTOR AT NINDS. AND IT'S A PLEASURE TO LAUNCH THE ROBERT NEWCOMB MEMORIAL LECTURE. I'M DELIGHTED TO WELCOME HERE INCLUDING THE FAMILY. THIS IS PART OF A SERIES OF ACTIVITIES AT NIH SUPPORTED BY THE ROBERT NEWCOMB FUND SO HONOR HIS MEMORY AND WE'RE VERY GRATEFUL FOR THE OPPORTUNITIES IT PROVIDES. DR. NEWCOMB BEGAN HIS SCIENTIFIC CAREER HERE AS A HIGH SCHOOL STUDENT, MADE A TREMENDOUS IMPRESSION ON HIM AND MOVED HIM INTO A SCIENCE CAREER, AND THAT EXPOSURE HAD LASTING EFFECT ON HIM AND THE FAMILY, HAS RECOGNIZED THAT AND SUPPORTS STUDENTS TO COME HERE IN THE SUMMER OR IN THEIR POST COLLEGE YEARS TO DO RESEARCH AND TRY OUT AS A CAREER, AND SO IN THE FRONT ROW ONE OF THE SCHOLARS HERE WORKING WITH SUSAN REY. TOOK GRADUATE STUDENTS AT THE UNIVERSITY OF HAWAII AND HE THEN WORKED AS A POST DOC AT STANFORD LOOKING AT THE ACTIVITY OF SEVERAL NEURO PEPTIDES. HE DISCOVERED SEVERAL NEURO TOXIC INS WHICH MADE IMPORTANT DISCOVERIES IN THE ROLE IN CAUSING DAMAGE AFTER AN ISSUE ISSUE CHEMIC STROKE. AND HE HAD MAJOR NEURO INTERESTS IN PEPTIDES. INTERESTS AND HIS CONTRIBUTION TO THE AREAS, EACH YEAR THE FUND WILL SUPPORT A LECTURER BY RECOGNIZED EXPERT IN ONE OF THESE GENERAL AREAS WHAT HAPPENED WE'RE PLEASED TO HAVE DR. DANIEL CHOQUET. THEY FEEL NIH IS THE BEST PLACE TO CONTINUE THE WORK. SO WE THANK THE FAMILY PRESENT TODAY AND HIS FRIEND AND COLLEAGUES WHO CONTRIBUTED TO SUPPORT AND MEMORIAL FUND. SO WITH THAT, I'M GOING TO TURN THE PODIUM TO INTRODUCE OUR SPEAKER. [ APPLAUSE ] >> THANK YOU FOR THE WONDERFUL INTRODUCTION AND ALSO THANK THE FAMILY. IT'S A GREAT PLEASURE FOR ME TO INTRODUCE DR. DANIEL CHOQUET AT THE UNIVERSITY OF BORDEAU, FRANCE. DANIEL WAS VERY DISTINGUISHED TRAINING AND RESEARCHED CAREER. HE OBTAIN HIS BACHELOR DEGREE IN ENGINEERING IN PARIS IN 1984. TO STUDY THE CHANNELS, ESPECIALLY THE POTASSIUM HE TOLD ME AND I AGREE, HE'S THE FIRST PERSON TO PERFORM AND MAKES SOME ORIGINAL DISCOVERIES THERE. HE THEN MOVED TO THE UNITED STATES FOR A FEW MONTHS, THEN WENT TO UNIVERSITY FOR POST-OP TRAINING TO STUDY THE RESPONSE TO EXTERNAL INVASION, MECHANICAL FORCE. OVER THE LAST TWO DECADES DANIEL HAS BEEN A PIONEER IN THE DEVELOPING OF THE HIGH RESOLUTION IMAGING APPROACH TO STUDY THE RECEPTORS AND IT HAS BEEN -- OF TRAFFICKING AND THE DYNAMICS. HIS FINDING HAS SHOWN THAT THESE RECEPTORS CAN -- THE MOVE IN THE MEMBRANE AND SUCH MOVEMENTS CAN HAVE PROFOUND EFFECTS. AND IN THESE KIND OF VIEWS AT THE BEGINNING WHEN I STARTED MY PHD RESEARCH IN 2002. THAT THESE RECEPTORS -- ENOUGH MEMBRANE. SO AT THAT TIME THE PEOPLE IN THE FIELDS USED TWO MAJOR APPROACHES, TWO POWERFUL APPROACHES, ONE IS USE ELECT ROWPHYSIOLOGY AND DANIEL IS AMONG THE FIRST TO STUDY RECEPTORS IN LIFE. IT'S VERY LONG LIST, I JUST MENTION A FEW INCLUDING A BRONZE AND A SILVER AWARD FROM THE NATIONAL CENTER OF SCIENTIFIC RESEARCH IN FRANCE AND HAS ALSO BEEN ELECTED INTO A SCIENCE ACADEMY AND HAVE SEVERAL TEACHERS AWARDS. TODAY HE WILL TALK ABOUT HIS MOST RECENT RESEARCH FROM HIS LAB OF NANOSCALE RECEPTORS IN SYNAPTIC PLASTICITY. >>> THANK YOU VERY MUCH FOR THIS VERY KIND INTRODUCTION. THANK YOU VERY MUCH FOR SELECTING ME FOR THIS SPECIAL LECTURE. I'M ACTUALLY EXTREMELY HONORED TO HAVE BEEN SELECTED FOR THIS LECTURE. THANK YOU AGAIN. I WILL SHOW YOU JUST IN A FUNERAL THAT ACTUALLY THERE IS SOME SURGEONEN DEPUTY TO THIS CHOICE THAT YOU SEE. SO I'M GOING TO BE TELLING YOU A VERY VERY RECENT STORIES, MOST OF IT BEING UNPUBLISHED ON THIS ROLE NANOSCALE ORGANIZATION IN THE SIGN-UPS. THE DYNAMIC OF THIS INVOLVES PROCESSES OF SYNAPTIC PLASTICITY. BEFORE GOING INTO THAT, LET'S TRY TO SEE WHAT'S THE LINK OF THIS LECTURE AND MY OWN EXISTENCE. YOU'RE GOING TO SEE THAT THERE ARE ACTUALLY LINKS THAT I DISCOVERED RECENTLY WHAT I WAS SELECTED FOR THIS LECTURE. ACTUALLY HAS BEEN MENTIONED JUST PREVIOUSLY THE ORIGINAL WORK OF ROBERT NEUCOMB. IT'S BEEN A MOTHER ORGANISM FOR MANY MANY YEARS AND THAT DOES ALLOW THE DISCOVERY OF MANY BASIC PROCESSES IN THE NERVOUS SYSTEM. IN PARTICULAR I'M SURE YOU'RE ALL AWARE OF THE PIONEERING WORK THAT ERIC CANDLE DID AND THAT WAS AWARDED THE MOBILE PRIZE IN 20 FOR HIS WORK ON THE SYNAPTIC MEMORY AND MOST OF IT HAS BEEN USED BY ROBERT NEWCOMB IN HIS WORK. THIS IS ONE OF THE PIONEERING PAPERS IN '64 TOGETHER WITH THIS FRENCH GUY, DR. TAUC. PART OF THIS WORK WON DONE AT THE INCONSTITUTE OF BOILOLIE . [, ARCACHON, FRANCE. FOR THOSE WHO DON'T KNOW WHERE ARCACHON, IT IS HERE. THIS IS THE LABS WHERE THE STUDIES WERE DONE. VERY NICE. YOU CAN GO FOR FOR RESEARCH IN YOUR SCIENCE BECAUSE IT'S NEXT TO BORDEAU AND BORDEAU IS ONE OF THE MAIN CENTERS FOR NEUROSCIENCE RESEARCH IN FRANCE. THAT'S ONE OF THE NEW BUILDING THAT JUST CAME UP, JUST MOVED IN THIS NEW BUILDING A FEW MONTHS AGO. THE STRENGTH REALLY STEMS DIRECTLY FROM THIS MARINE LABORATORY IN ARCACHON. THEN MOVED TO BORDEAU AND HELPED FOSTER ALL OF THE NEUROSCIENCE. THERE'S A DIRECT LINK BETWEEN THE WORK NEWCOMB DID ON THE MARINE LAB AND THE COMMUNITY. THERE'S ANOTHER LINK MORE RECENT FROM THE WORK OF ROBERT NEWCOMB BECAUSE THIS WORK, WORK FOR MANY OTHERS OF COURSE, HAVE ESTABLISHED IT'S SO IMPORTANT FOR RAIN FUNCTION AND RECEPTORS, URGING SIGN-UPS IS REALLY THE OBJECT I'VE BEEN WORKING ON OVER THE LAST 20 YEARS. SO LET ME GO NOW DIRECTLY INTO THE SCIENTIFIC PART OF THE STOVE. TRYING TO UNRAVEL THE BASIC PROCESS OF THIS AND HOW IT'S REGULATING AND MEMORY. SO AS MOST OF YOU KNOW, I'M SURE, MOST EXCITED THROUGH SIGN APTIC, NAMED ON SPECIAL ORGANISMS CALLED SPEUPS. MOST OF THE WORK I'M GOING TO SHOW YOU HAS BEEN DOWN IN HIPPO CAMPO NEURONS. ALSO DONE ON SLICES OF BRAIN SLICES OF HIPPO CAMPUS. SOMETHING STUDIED THE LAST 20 YEARS IS THE PLASTICITY AND ORGANIZATION OF THE SPIEPS BECAUSE THERE'S BEEN HYPOTHESIS ALREADY MORE THAN 40 YEARS AGO THAT ACTUALLY PLASTICITY OF SIGH -- SYNAPTIC TRANSMISSION. ON THE SIGH -- SCNANSIS, WE'LL BE TALKING ABOUT ONLY ONE REKRS CETTIDE. WE TALK ABOUT DYNAMICS, THAT MEANS THAT WE ARE GOING TO USE A LOT OF IMAGING IMAGES AND REALLY TALKING ABOUT THE IMAGING IF YOU USE CLASSICAL IMAGING METHODS, YOU KNOW THEY ARE USUALLY DIFFERENTIATED BY DEFRACTION. BECAUSE THE SPEUPS ARE VERY SMALL, IF YOU USE DECLASSICAL, YOU GET VERY LIMITED IN TERMS OF BEING ABLE TO DECIPHER. IF YOU LOOK AT THIS MICRO GRAPH HERE, BEFORE SIGN SYNAPTIC COMPARTMENT. THAT'S WHY THE EVENT OF SINGLE MONTHLY CULTURE IMAGING AND LATER ON THE EVENT IN WHICH YOU GET INTO IN THIS TOPIC HAVE BEEN ABLE TO LOOK AT THE DYNAMIC RESOLUTION. SO LET'S FIRST CONCENTRATE ON THESE EMPIRE RECEPTORS. THEY HAVE A VERY BIG DOMAIN HERE. LIES HERE. YOU CAN ACTIVATE THE RECEPTOR BUT ACTUALLY BECAUSE THEY ARE FORCE OF UNITS THAT FORM THE CENTRAL TUNNEL, YOU ACTUALLY HAVE EVEN THE LARGER CONDUCTENTS AND BINDING LEADS TO OPENING THE CHANNEL AND EXCITATION OF THE CELL. ANOTHER IMPORTANT FINDING THAT HAS COME IN THE LAST DECADE IS THOSE RECEPTORS DO NOT COME ALONG. THEY ARE SURROUNDED BY A VARIETY OF UNITS THAT REGULATE BOTH THE FUNCTION, THE TRAFFICKING OF THESE ION CHANNELS AND IN PARTICULAR ABOUT ONE HANDICAP HIS FAMILY THAT WE THINK PLAYS VERY, VERY IMPORTANT ROLE IN PARTICULAR IN PROCESSES. NOW IF WE LOOK AT THE SYNAPSE. I'M TAKING THE SCHEME HERE WHICH IS A BIT OUTDATED ON PURPOSE JUST TO HIGHLIGHT A FEW OF THE VERY IMPORTANT NEW PRINCIPAL THAT I THINK ARE EMERGING NOW ON THE RELATION OF THE RECEPTORS AND THE FUNCTION OF THESE SYNAPSES. THE RECEPTORS ON THIS SMALL CHANNEL, WE KNOW KNOW THAT THEY HAVE A DOMAIN THAT NEARLY TOUCH TOUCHES SYNAPTIC MEMBRANE. IN THE PAST FOR A WHILE IT'S THOUGHT THAT RECEPTORS FUSES WITH THE MEMBRANE THAT RECEPTORS WOULD BE ACTIVATED. WHEN INDEED THERE'S PRETTY GOOD EVIDENCE NOW THAT THAT'S PROBABLY NOT THE CASE AND BECAUSE OF THE VERY ACTIVITY IN THE OPENING OF THIS CHANNELS ALSO TOGETHER WITH THE FACT THAT THE AFFINITY OF THESE RECEPTORS IS LOW. ON AVERAGE IT'S USUALLY AROUND THE 200 MICRO MOLAR. THAT MEANS THAT PROBABLY THE AREA OVER WHICH RECEPTORS GET ACTIVATED BY RELEASE OF A SINGLE PHYSICAL IS PROBABLY MUCH SMALLER. NOBODY'S EVER BEEN ABLE TO MEASURE IT DIRECTLY BUT IF YOU DO MODELING TO SIMULATE HOPING OF THESE CHANNELS AND THAT'S ONE SORT OF MODELING. BUT REALIZE THAT PROBABLY RECEPTORS GET ACTIVATED ONLY IN AN AREA WHICH IS LESS THAN 100 IN DIAMETER. AND THAT INDICATES THAT IF YOU ARE A RECEPTOR, IF YOU ARE HERE IN FRONT OF THE SIDE OR IF YOU ARE HERE A COUPLE HUNDRED NANOMETERS AWAY, THAT MAKES A HUGE DIFFERENCE IN FUNCTION. THAT WAS THE RATIONALITY FOR US WITH THE RECEPTORS. THE OTHER THING, AND THAT HAS BEEN KNOWN FOR A VERY LONG TIME IS THAT HIS SYNAPSE IS EXTREMELY DYNAMIC. ITS ORGANIZATION IS EXTREMELY DYNAMIC AND MANY MANY LABS AND SEVERAL IN THE AUDIENCE HERE HAVE PROPOSED THAT REGULATION OF THE DYNAMIC OF THE ELEMENTS IS ACTUALLY ONE OF THE MECHANISM THAT UNDER LIES VARIOUS PROCESSES. SO I'M GOING TO JUMP MANY MANY SLIDES OF INTRODUCTION IN SOME SENSE TO GO TO WHAT'S THE CURRENT VIEW THAT'S ACCEPTED IN THE FIELD IN REGARDS TO THIS ASPECT. SO INITIAL I WOULD SAY 20 YEARS AGO IT WAS THOUGHT RECEPTORS WERE ONLY LOCALIZED RIGHT IN FRONT. ACTUALLY, WE KNOW THAT'S NOT TRUE. WE KNOW THERE ARE RECEPTORS EVERYWHERE. I'LL COME BACK TO THAT. SO FIRST SERIES WHAT WE'RE GOING TO TALK ABOUT, THIS PROCESS TO WHICH HIGH FREQUENCY STIMULATION LEADS TO RESPONSES THAT RESOLVE A LONG TIME IN THE POST SYNAPTIC MEMBRANE. HISTORICALLY THIS HAS BEEN ATTRIBUTED TO CHANGES IN TRANSMITTER AND THESE HAVE NOT BEEN THOUGHT TO BE RELATED TO THE RECEPTORS. I SHOW YOU WE HAVE STRONG EVIDENCE. EITHER THE PROCESSES OF LONG-TERM POE THEN HALATION. WHEREBY DECREASING OF SYNAPTIC TRANSMISSION, SO THIS HAS BEEN ESTABLISHED MORE THAN TEN YEARS AGO, AND READING THE WHOLE GANG, THE FIELD HAS BEEN TO TRY TO UNDERSTAND HOW ACCOUNT SIGN-UPS REGULATE SO RAPIDLY AND MAINTAIN FOR SUCH A LONG TIME GIVEN NUMBERS OF RECEPTORS AND TO CUT MANY MANY PAPERS SHORT, I WOULD SAY, THE SUMMER REVIEW NOW IS THIS PROCESS OF RECEPTOR TRAFFICKING THAT ACTUALLY HAS BECOME PRETTY COMPLEX WHEREBY WE KNOW NOW THESE CAN BE REFUSE IN THE PLANE OF THE MEMBRANE AND THE CURRENT VIEW IS REGULATING RECEPTOR NUMBERS THERE SHARE WHILE THEY PLAY THEIR FUNCTION REALLY IS THE RESULT HAMILTON A VERY, VERY COMPLEX SET OF INTER DEPENDENCY EVENTS SO TOGETHER WITH REGULATION OF THE WAY THEY BIND TO SCAFFOLD ELEMENTS AND REGULATION BY YOUR PHYSICAL FUNCTIONS. SO WHAT ARE THOSE VALUES TRAFFICKING PATHWAYS? FIRST OF ALL, I WOULD SAY IN TERMS OF THE RECEPTORS IS THE ONE OF TRANSPORT. WHAT YOU SEE HERE IN GREENS ARE SYNAPSES. I WON'T TELL YOU ABOUT THESE RESULTS TODAY, JUST TO TELL YOU THAT THERE'S BEEN ACTUALLY VERY LITTLE WORK BECAUSE THEY ARE PROBABLY JUST A VERY STRONG NUMBER OF RECEPTORS PER PHYSICAL AND IT'S BEEN VERY, VERY DIFFICULT FOR PEOPLE. NOW FEW LABS HAVE ACTUALLY MANAGED TO DO THAT. SO THESE RECEPTORS AND THEN AT SOME POINT THEY GET THOSE EXCITERS. IT'S NOT REALLY WELL KNOW. THERE'S A DEBATE ON WHETHER THOSE ARE IN THE DRIVE OR DIRECTLY IN THE SPINE HEAD. THERE'S BEEN EARLY RESULT TEN YEARS AGO SHOWING DIRECTLY THE RECEPTORS USING PH SENSITIVE. YOU SEE THESE HOT SPOTS. IT SEEMS THAT MOST BUT THERE ARE SOME REPORTS IN THE SPINE AND IT'S STILL AN OPEN MATTER OF DISCUSSION. THE THIRD PATHWAY IS THE ONE THAT WE EVIDENCED NOW NEARLY 20 YEARS AGO IS THIS LATERAL DEFUSION OF THE PLANE IN THE MEMBRANE. YOU SEE HERE SINGLE DOTS BOUND TO THE DOMAIN OF EMPIRE RECEPTORS. YOU SEE THIS DIFFUSE ON THE PLANE OF THE MEMBRANE AND THEN THEY CAN SIGN UP AND THEY ACTUALLY DO THAT ALL THE TIME. SO SO THE IDEA REALLY NOW IS -- THE CONCEPT IS REALLY THAT REGULATING RECEPTOR NUMBERS MEANS REGULATING ONE OF THESE PROCESSES. BECAUSE OF COURSE THEY ARE ALL I INTER-LINKED, IT'S IMPOSSIBLE TO TELL ONE FROM THE OTHER. SO I'M GOING TO TELL YOU THREE STORIES ABOUT THIS, ONE I'M GOING TO GO PRETTY QUICKLY OVER BECAUSE IT WAS REVENGE PUBLISHED ALREADY BUT IT'S IMPORTANT FOR THE REST. THEN I'M GOING TO TELL YOU TWO UNPUBLISHED STORIES ON THE ROLE IN LONG-TERM PLACE IS TEE. A SHORT SUMMARY OF WHAT WE KNOW RIGHT NOW. THERE'S BEEN VERY STRONG BY MANY LABS TO LOOK AT THE NANOSCALE ORGANIZATION OF RECEPTORS. ABOUT THREE YEARS AGO, FOUR YEARS AGO, THE GROUPS PUBLISHED WORKS ON THESE AMPA RECEPTORS. TO LOOK AT THE, I WOULD SAY, 1500 AND THE BIG SURPRISE WAS THAT IF YOU LOOK AT THE SPINE, EMPIRE RECEPTORS SEEM NOT TO BE RANDOMLY DISTRBUTED BUT IN FACT SEEM TO BE HIGHLY CONCENTRATED IN SMALL HOT SPOTS. WHAT YOU'RE LOOKING AT IS THE TECHNIQUE. IT'S A SINGLE-MONTHLY CULTURE PHASE. IMAGE THAT GIVES YOU A RESOLUTION. AND YOU SEE THAT IS VERY HIGH, HOT SPOTS OF RECEPTORS. IN BETWEEN RECEPTORS YOU CAN EMPIRE RECEPTORS BUT THEY ARE MORE DIFFUSED HERE. SO THIS IS ON FIXED NEURONS. WHAT'S THE DISTRIBUTION LIKE. TO LOOK AT THAT, ANOTHER APPROACH THAT YOU CAN USE LIKE NEURONS. IT'S CALLED UNIVERSAL PAINT. IT'S JUST ANOTHER BASED TECHNIQUE BUT THAT'S VERY USEFUL BECAUSE YOU CAN USE IT TO LOOK AT ENDOGENOUS RECEPTORS. IT'S NOT TURF. SO YOU HAVE A SHEET OF ABOUT A FEW MIGHT KRONS THAT'S ILLUMINATED AND THEN YOU PUT IN YOUR -- AND DILUTE CONCENTRATIONS. IT'S GOING TO DIFFUSE TO THE CELL SURFACE AND THEN YOU'RE GOING TO BE ABLE TO TRACK THE MOVEMENT AND THEN THEY ARE GOING TO BE REPLACED. THE BEAUTY OF THIS APPROACH IS REALLY THAT ONE YOU CAN TRACK ENDOGENOUS RECEPTORS AND THE OTHER USING DYES TO LABEL THE LABELS. THIS ALLOWS YOU TO HAVE LONG TRACK. SO IF YOU DO THAT, THE RAW DATA THAT YOU GET, THESE ARE ALL SINGLE MOLECULES. THEY LAY ON THE NEURAL SURFACE AND YOU CAN TRACK THEM WITH VERY HIGH ACCURACY. YOU GET THE ACCURACY. SO THEN YOU CAN RECONSTRUCT THE LOCALIZATION OF THESE RECEPTORS AND ALSO THEIR TRAY JECTERIES. YOU WOULD SEE THIS TYPICAL HOT SPOTS HERE LIKE ONE HERE, FOR EXAMPLE, THIS RED DOT IS A BIGGER HOT SPOT OF RECEPTORS BUT YOU ALSO HAVE RECEPTORS, AND IF YOU LOOK AT THE TRAJECTORY OF THE RECEPTORS, YOU SEE THEY MOVE ALL OF THE TIME. AT LEAST PART OF THEM MOVE ALL THE TIME AND SOME OF HOME ARE IMMOBILE. THIS IS A -- THOSE RECEPTORS HERE ARE MOBILE OR MOVE EXTREMELY SLOWLY. THEY LOVE VERY LITTLE BUT THAT IN BETWEEN THOSE RECEPTORS ARE ACTUALLY VERY FAST. VERY QUICKLY. WHAT WE THINK NOW AND I WOULD SAY PRETTY WELL ACCEPTED IN THE FIELD NOW. IT'S BEEN REPRODUCED SOME OF THEM ARE IN THESE CLUSTERS PROBABLY AROUND 20, 30 RECEPTORS AND THEN IN BETWEEN THOSE CLUSTERS, ANOTHER POPULATION OF EXTREMELY HIGHLY MOBILE RECEPTORS ONCE AGAIN. THAT'S ANOTHER DISTRIBUTION. WHERE YOU SEE THESE TWO BUMPS. THOSE MOBILE RECEPTORS EXTENDS VERY EASILY BETWEEN THE SIGN SYNAPTIC MEMBRANE. REGULATES THESE CHANGE. TO SO I WOULDN'T KNOW THAT. WHAT I'M GOING TO TELL YOU NOW, REALLY WHAT COULD BE THE FUNCTION OF THE MOVIE, THE RECEPTORS IN THE TRANSMISSION IN PARTICULAR OF SYNAPTIC PLASTICITY. WELL, THAT'S REALLY GOING TO BE STORIES BUT WHICH HAVE BEEN BY THE GROUP, MAINLY SPEARHEADED BY ANDREW PENN. LOTS OF SLICE WORK AND ALSO BEHAVIR. TRYING TO LOOK AT THE ROLE OF THIS MOBILE RECEPTORS, HAD THE IDEA TO LOOK AT THE FUNCTION OF THESE MOBILE RECEPTORS TO CROSS-LINK THEM USING TWO LAYERS. WE COULD ACTUALLY SHOW VERY OBVIOUSLY THAT THE MOVEMENT OF SURFACE RECEPTORS AND THEN LOOKED AT THE IMPACT ON PROPERTIES OF SYNAPTIC TRANSMISSION. I SHOW YOU MORE DATA OF THAT LATER ON WHEN YOU CROSS-LINK RECEPTORS TO PREVENT THEIR MOVEMENT, SO DEPRESSED, BUT THEN HE HAD THE IDEA OF PLASTICITY AND THERE HE WAS EXTREMELY SURPRISED TO SEE THAT BY DOING YOUR PATCH COLLEGE PT RECORDINGS THAT IN THESE CULTURES AND TO DEPRESS A LITTLE BIT APPLYING THESE CROSS-THINKING AGENTS HE SAW A BIG INCREASE IN DEPRESSION. THIS IS REALLY THE HALLMARK OF A CHANGING TRANSITORY LEASE. THE QUESTION WAS REALLY OUT OF THE ORGANIZATION OF RECEPTORS AND THE SYNAPTIC MEMBRANE THAT IS SUPPOSEDLY TO APPRECIATE THE CHANGE. SO TO RULE OUT THE FACT THAT THIS WAS A PRE SYNAPTIC, IN CONTROL CONDITIONS AND WHEN YOU CROSSING THE RECEPTORS, YOU SEE THERE ARE THESE BIG INCREASE IN THE DEPRESSION. INDEED CHANGING THE MOBILITY OF THE RECEPTORS WAS CHANGING THE SHORTER PLACE IS TEE. ALTHOUGH THIS WAS WELL-PUBLISHED, TOLD ME THAT THE ONLY REASON HE PUBLISHED THE PAPER IS HE THOUGHT THE IDEA WAS CRAZY ENOUGH TO BE PUT FORWARD IN THE COMMUNITY. I WOULD SAY MOST FEEL THAT BELIEVE THAT CHANGING THE MOVEMENT OF RECEPTORS COULD CHANGE PLASTICITY IN A FEW MILLISECONDS. I THINK WE'RE COMING UP NOW WITH I FOCUS ON HOW THIS COULD ACTUALLY WORK AND THAT'S WHAT I'M GOING TO TELL YOU. THE IDEA THAT WE HAVE IS THAT THESE EMPIRE RECEPTORS ONCE THEY GET ACTIVATED, THEY GET DESENSITIZED AND SO WE GET THE IDEA THAT MAYBE EXCHANGE OF RECEPTORS AND THE PARTICULAR EXCHANGE OF DESENSITIZER RECEPTORS, WITH THE IDEA OF BEING WHEN RECEPTORS ARE MOBILE, YOU GET MORE DEPRESSION AND OF RECEPTORS ARE MOBILE YOU GET MORE OF A CHANCE MOST PEOPLE THOUGHT AT THE TIME, SO JUST ANOTHER WAY TO LOOK AT THAT IS LOOKING AT IT FROM THE TOP. THE IDEA IS THAT MADE THAT RELEASE. ACTIVATE RECEPTORS VERY QUICKLY. OR IF THEY ARE MOBILE YOU CAN HAVE, YOU CAN GET MORE OR LESS. ONE OF THEM BEING HOW COME RECEPTORS MOVE FAST ENOUGH TO LISTEN TO THIS IN THIS AREA, THIS IS SOMETHING THAT OCCURS IN MORE IN TACT ISSUES AND ALSO FOR THIS MODEL TO HAPPEN, THE HIGH FREQUENCY OF RELEASE ON THE SAME LOCATION IN ORDER TO HAVE THE SAME AREA OF RECEPTORS BEING ACTIVATED. SO THAT'S WHERE IT ACTUALLY CAME THROUGH AND REALLY VERY HIGH ENERGY TRIED TO ANSWER SOME OF THESE QUESTIONS, AND IN PARTICULAR TRIED TO MOVE THIS EXPERIMENT. INITIALLY WHEN YOU STARTED TO LOOK, TRIED TO DO THE SAME EXPERIMENT IN SLICES, HE DIDN'T MANAGE. IN PLACES HE WAS USING, AND TO USE A SMALLER THAT WOULD TEN TRAIT WELL IN SLICES. AND THEN THE IDEA WAS THAT THE RECEPTORS IN ORDER TO BE ABLE TOLL USE THIS CROSS-LINKING TOOL. AND SO WHEN YOU USE THE RECEPTOR, EXPRESS IT WITH RESIDENT. AND THEN YOU CAN MAKE IT TO THE CELL SURFACE AND USE RECEPTORS. WE HAVE TO CHECK SEVERAL THINGS, OF COURSE, USING THE SYSTEM. AND SO WE WENT ON THE SINGLE CELL OPERATION OF EITHER TWO OR ONE OR BOTH OF THEM. SO A WHOLE SERIES OF CONTROLS, FIRST OF ALL, THESE RECEPTORS GET BIO TEEN. YOU CAN LABEL THEM VERY EASILY. SURFACE STAIN OF RECEPTORS. IN ALSO BLOCK SURFACE MOBILITY. WHAT YOU SEE HERE ARE TRACES OF FRAB. YOU SEE THE BASIL RECOVERY CURVE FOR CONTROL SITUATION. YOU SEE ABOUT HALF OF THE RECEPTORS ARE MOBILE. WHEN YOU APPLY YOU SEE YOU HAVE MUCH LESS RECOVERY. VERY IMPORTANT CONTROLS IS WHAT DOES THE STAGGING AND THIS CROSS-THINKING DO TO THE BIO PHYSICAL PROPERTIES OF THE RECEPTORS, AND AS WE HAD FOUNDED THE ANTIQUITY, WE ACTUALLY FOUND THAT REALLY DOESN'T ANYTHING WE CAN DETECT. USING FAST APPLICATION TO LOOK AT THE BIO PHYSICAL PROPERTIES OF THIS RECEPTORS. EITHER TAGGED OR NOT CROSS-LINK AND WHICH EVER BY PARAMETER YOU LOOK AT, YOU DON'T SEE ANY EFFECT OF THE CROSSING. THEY SEEM PRETTY IMMUNE, DO THEY MAKE IT TO THE SIGNUPS? THE ANSWER IS YES. WE COULD CHECK THAT BY WORKING ON TWO MAPS. YOU SEE THOSE RECTIFY VERY STRONGLY. YOU HAVE NO CURRENTS -- AND SO WHEN YOU PUT THAT INTO A TUBE, YOU RECOVER A NORMAL -- KIND OF AN INTERESTING FEATURE WE WERE DISCUSSING THIS MORNING. IT'S ACTUALLY INITIAL TRIED TO DO THAT EXPERIMENT AND RECOVERING THE RESPONSE. THIS ACTUALLY DIDN'T WORK. WE COULD NOT RESTORE TRANSMISSION TIED WITH GFP, AND WE KNOW NOW WORK HAS SHOWN THAT UA-1 JFP CANNOT MAKE IT WELL TO THE SIGNUPS. KIND OF AN INTERESTING OBSERVATION. A FEW FURTHER CONTROLS. WHAT HAPPENS WHEN YOU CROSS-LINK THOSE RECEPTORS? BASICALLY NO CHANGE IN SITABILITY. IT SEEMS ON CROSS-THINKING THEM DIDN'T CHANGE THE BASE OF PROPERTIES OUTSIDE THAT TRANSMISSION. THEN WHAT ABOUT AUTHORITIENED PLASTICITY? WE WERE VERY PLEASED TO SAY SHORTENED PLASTICITY WAS ALSO MODIFIED IN A BIT OF THE SAME WAY. SO, BUT AS YOU'LL SEE, THAT'S SOMETHING THAT ONLY HAPPENS IN PRETTY PECULIAR CONDITIONS. SO THESE ARE RECORDINGS IN THE HIGH CALCIUM, MAGNESIUM RATIOS. THIS IS CONTROL CONDITION, THEN WHEN YOU YOU SEE A CHANGE ABOUT 25% IN THE DECREASE AND IF YOU DON'T EFFICIENT ENTRANCE SALES YOU DON'T HAVE A CHANGE IN THE -- INTERESTINGLY IF YOU NOW WILL GO TO CONDITION, YOU DON'T SEE THIS EFFECT, THESE ARE A CONDITION, YOU HAVE MULTIPLE AS EXPECTED AND THIS IS NOT AFFECTED. SO IN SUMMARY WE COULD RECAPITULATE. AND IT SEEMS TO BE RELATED TO THE RELEASE. >>> A FEW OTHER POINTS HERE WHICH ARE OF INTEREST. IN PARTICULAR THIS IS REALLY DUE TO THE ENSIZATION. SO THAT'S THIS EXPERIMENT. A CONTROL RECORDING, APPLYING A TRAIN OF SYSTEM LIE. WHEN YOU APPLY, INCREASE DEPRESSION HERE, IN PRESENCE WHICH ACTUALLY CHANGES THE RECEPTORS FOR GWILL YOU TELLIMADE. THE OVERALL CONCENTRATION AND NOW THAT PREVENTS RECEPTOR, YOU COMPLETELY SUPPRESSED THIS EFFECT. SO IT REALLY SEEMED THAT THERE WAS A DIRECT LINK BETWEEN THIS AND THIS EFFECT ON SHORT-TERM PLACE IS TEE. THIS IS A PRETTY IMPORTANT EXPERIMENT BECAUSE SENSE OF EFFECT ON SHORTENED PLACE IS TEE WAS PREVIOUSLY USED AS AN ARGUMENT TO SAY THAT IT DOES NOT OCCUR OR DOESN'T PLAY A ROLE AT THE SYNAPSES. SO TO MAKE SURE THAT WE ARE REALLY LOOKING AT THE SYNAPTIC PHENOMENON, WE WANTED TO GO FURTHER AND ANDREW HAD THE IDEA TO USE A VARIETY OF MUTANTS THAT CHANGED THE RATE. SO HE USED TWO MUTANTS THAT DO NOT DESENSITIZE AND THEN THAT RECOVERS VERY SLOWLY FROM THE SENSE ACTIVEIZATION. YOU HAVE HERE THE VERY SLOW RECOVERY. AND SO THE PREDICTION WAS THAT IS LINKED TO THEIR MOBILITY AND TO SHORTEN PLACE IS TEE, THEN THOSE MUTANTS SHOULD HAVE AN IMPACT ON SHORTENED PLACE IS TEE. SO WE USED THOSE MUTANTS IN THE CELLS AND WE USED THE CELLS HERE WHICH ARE NOT -- ONLY ONE CELL IS TRANCE EFFECTED AS I CONTROLLED PATHWAY THIS PARTICULAR CELL SUGGESTING THAT RECEPTORS DON'T DESENSITIZE AS HAVING RECEPTORS THAT RECOVERS VERY CLOSELY ARE THE, BUT THEN IF YOU TAKE THE SAME CELLS TO TRUSTING THE RECEPTORS, THEN YOU SEE A HUGE DEPRESSION FROM THIS SENSITIZATION. YOU WOULD ALSO SEE IT'S NOT DESENSITIZED. I WOULDN'T BE THERE IF HADN'T WORKED. YOU SEE NOW THAT WHETHER YOU USE CONTROL CONDITIONS OR CROSS-THINKING CONDITIONS YOU GET THE SAME TYPE OF RESPONSE. SO ALTOGETHER WE CAME UP WHEREBY YOU REALLY HAVE AN INTERPLAY AND THEIR RATE OF RECOVERY FROM THIS. BASICALLY, ARE GOING TO BE ACTIVATED AND SO RESENT ACTIVITIES NOT GOING TO PARTICIPATE. HAVE A STRONG IMPACT IS GOING TO HELP RECOVER FROM DEPRESSION DUE TO RECEPTOR DESENSITIZATION ALLOWING THIS FASTER RECOVERY, AND THEN IF YOU HAVE AN UNBETWEEN STATE AND FAST RECOVERY FROM THIS DESENSITIZATION WE CANNOT HAVE AN IN BETWEEN THING. >> TO FINISH THE STORY ON SHORTENED PLACE IS TEE, ON THE PAPER WE JUST PUBLISHED LAST YEAR WHICH ACTUALLY IS WHY RECEPTORS CAN MOVE FAST ENOUGH. AND SO THIS QUESTION WAS REALLY HOW DID, IS THERE ANY LINK? THE IDEA BEING IS THERE SOMETHING SPECIAL THAT HAPPENS THAT ALLOWS THIS FASTER EXCHANGE. SO WAS TO DESENSITIZE EMPIRE RECEPTORS AND SEE WHETHER THIS HAD ANY IMPACT ON RECEPTOR MOVEMENT. HE DID THOSE EXPERIMENTS, AND THEN BASICALLY BEING CONDITIONED WHERE HE'S BLOCKED ANY TYPE POSSIBLE AND LOOKING AT THE BEAUTY OF THE RECEPTORS, YOU SEE THAT APPLICATION ACTUALLY STRONGLY INCREASE THE MOVEMENT OF THE RECEPTORS. LOOKING AT THE DISTRIBUTION, YOU SEE THAT ON THEIR GLUTAMATE. AND THOSE DEPENDENT PROCESS THAT YOU STOP SEEING, APPEARING AFTER A FEW TENTHS OF MICRO MOTOR. SO IS IT REALLY RELATED TO RECEPTOR DESENSITIZATION? SO BEFORE THAT THEY MADE USE OF THOSE SAME MUTANTS PLUS MUTANTS THAT GET NOT THE -- OR MUTANT THAT DON'T DESENSITIZE. AND WHAT'S ALREADY FROM THE TRACKS OF THE RECEPTORS YOU SEE HERE THAT THE CLOSED RECEPTORS DIFFUSE MUCH LESS. YOU SEE YOU HAVE MUCH MORE MOBILE RECEPTORS WHEN THEY ARE DESENSITIZED. SO HOW COULD IT BE? HOW COULD A CHANGE IN THE FORM OF EMPIRE RECEPTORS CHANGE THEIR RATE OF MOBILITY? SO THOSE MOVE IN THE MEMBRANE. IF YOU WANT TO THEIR MOBILITY, REALLY THE ONLY WAY YOU CAN DO THAT IS BY CHANGING THE WAY THEY ARE ANCHORED TO SOME STABLE ALMOST. SO IT WAS PRETTY OBVIOUS THAT IF THAT WAS TO HAPPEN, THAT WAS MEANING THAT THE CONFIRMATION OF THE RECEPTORS WAS CHANGING IN SOME MANNER. ONE TYPE OF ELEMENT COULD IT BE? AS I TOLD YOU THE EMPIRE RECEPTOR DOESN'T COME ALONE. THERE'S A PRETTY INTERESTING COMPLEX WHICH IS THE ASSOCIATION MADE BETWEEN THE EMPIRE RECEPTOR AND THE TOP, SOME TYPE OF PROTEIN, ONE OF ITS MEMBERS. THAT ACTUALLY ALLOWS BINDING OF THE COMPLEX AND ALLOWS IN THE MAP WAY. ACTUALLY THIS WHOLE COMPLEX WAS CRYSTALLIZED VERY RECENTLY. IN FACT AFTER WE DONE OUR OWN WORK BUT YOU SEE IT EXPLAINS A LOT OF THINGS. YOU SEE STAR GAZING REALLY STAYS HERE. REALLY LIE JUST BELOW THE DOMAIN OF THE RECEPTOR AND WHAT THIS OTHER GROUP SHOWED IS THAT WHEN THE RECEPTORS GET OPEN, CHANGING THEIR INTERACTION WITH STAR GAZING. SO THE IDEA WAS WHEN, THEY HOW BINDING FROM THE STAR GAZING. SO WE CHECKED THAT INITIALLY WITH BIO CHEMISTRY. AND IT'S PRETTY OBVIOUS HERE THAT YOU PUT DOWN MUCH LESS STAR GAZING THAN WHEN YOU ARE IN THE CLOSED CONFIRMATION THAT QUANTIFIES YOU. SO ANOTHER WAY TO LOOK AT THAT MORE DIRECTLY WAS TO SEE INDEED IF WE PREVENT THE DISASSOCIATION BETWEEN THE RECEPTORS AND THE TALK AND WE PREVENT THIS EFFECT OF MOBILITY AND CHANGE IN SORT OF PLACE IS TEE. SO FIRST OF ALL, CONTROLLED CONDITIONS FOR EXPRESSING THE RECEPTORS. YOU SHOULD LOOK AT TRAINS, YOU SEE CROSS-LINKING THE RECEPTORS, AS I'VE SHOWN YOU PREVIOUSLY. WHAT IF WE PREVENTED AND WE COULD ACTUALLY DO THAT BY USING A TOOL. BY FUSING THE RECEPTOR OF STAR GAZING. YOU PREVENT ANY TYPE OF POSSIBLE DEASSOCIATION, AND SO HERE AS SEVERAL INTERESTING PROPERTIES. FIRST OF ALL, IT MOVES LESS THAN DOES THE Y TYPE. YOU SEE THESE MOBILE RECEPTORS HERE SO THEY ARE ALREADY QUITE MOBILIZED. YOU SEE THAT SENSE OF CROSS-LINKING. THE RESPONSES ARE INDEED DEPRESSED. IF YOU CROSS-LINK, THEY DON'T DEPRESS MORE. AND SO SUMMARY FOR THIS IS THE FOLLOWING WHAT WE BELIEVE THAT WHEN THE RECEPTORS GET DID HE SENSITIZED, YOU HAVE A HUGE CHANGE AND THAT SOMEHOW PUSHES UP STAR GAZING AND ALLOW FREEING THE RECEPTOR OUT. IN SUPPORT OF THAT IS THIS NICE SERIES FROM A GROUP. YOU HAVE HERE FROM THESE EMPIRE RECEPTORS. THAT'S THE FORMATION. THAT'S THE OPEN CONFIRMATION AND THAT'S DESENSITIZED FORMATION. IT'S NOT HARD TO IMAGINE THAT THIS HAS A STRONG IMPACT TO THE INTERACTION OF THE RECEPTORS. SO THAT'S WHY WE COME BACK WITH OUR MODEL. THERE IS SOMETHING VERY SPECIFIC THAT CAN ESCAPE VERY QUICKLY, THAT CAN MOVE ALLOWING RECEPTORS COME IN SO THAT THIS HELPS TUNE OF FREQUENT WEDNESDAY. IT'S ABOUT A 25% REDUCTION OR CHANGE IN THE SHORTENED PLACE IS TEE BUT WE THINK THIS COULD HAVE VERY STRONG IMPACT ON THE IF I SEEOLOGY OF THE BRAIN AND THAT'S WHAT WE HAVE TRAINED TO INVESTIGATE. LET ME SWITCH NOW TO THE LAST PART OF THE PRESENTATION, SWITCHING TO THE ROLE OF AMPAR SURFACE DID I HAVE FUSION IN LONG-TERM PLACE IS TEE. I'M GOING TO GO QUICKLY THROUGH PUBLISHED WORK. ON THE ROLE OF AMPAR SURFACE DID I HAVE FUSION IN LONG-TERM PLACE IS TEE. TO LOOK AT THAT WHAT WE'VE BEEN DOING A APPLYING HIGH FREQUENCY STIMULUS. WHAT WE HAD FOUND MANY YEARS AGO IS WHEN YOU APPLY, THEY TEND TO IMMOBILIZE VERY QUICKLY. WE WORKED OUT MORE OR LESS THE PATHWAY FOR THIS. WE KNOW IT'S KEPT AN INFLUX TO RECEPTORS AND REGULATING SPHREUKS OF THE RECEPTORS WITH STAR GAZING. THIS IS JUST ONE SHOWING YOU WITHIN A FEW HUNDREDTHS, YOU CAN MOBILIZE VERY STRONGLY THE RECEPTOR. WE KNOW THIS IS ACTUALLY DUE TO A REGULATION BETWEEN THIS INTERACTION , BETWEEN STARGAZIN. THIS HAS A BINDING MOTIF HERE. THIS SENSOR. WHAT'S BEEN SHOWN IS THAT THE STRETCH HERE ACTUALLY REGULATES THE BINDING OF PS-95. WHY? THAT'S BECAUSE THE GROUP HERE ACTUALLY SHOWED THAT PSD-95 IS PERPENDICULAR TO THE MEMBRANE, AND SO WE CAME UP WITH THE IDEA THAT MAYBE BY -- YOU REGULATE THE BINDING TO THE MEMBRANE AND YOU CAN ALLOW IN THESE PHOSPHATES TO THE MEMBRANE, YOU CAN ALLOW BINDING TO DIFFERENT DOE MAINS AND MOBILIZE THE RECEPTORS. >> WE SHOWED THAT DIRECTLY USING FRET. JUST BY CHANGING THE LENGTH OF STARGAZIN YOU CAN CHANGE THE INTERACTION AND ALSO JUST BY CHANGING THE CHARGE OF PSD-95. JUST THE SUMMARY OF THIS SMALL PIECE OF WORK HERE, THE IDEA IS RECEPTORS DIFFUSE WHEN COMES IN AND THAT ALLOWS STRONGER BINDING OF THE RECEPTORS. SO THAT WAS SHOWING THAT REALLY INFLUX AND MOBILIZATION AND THERE'S PROBABLY A RECRUITMENT OF THE RECEPTORS IN THE SIGN-UPS. THE QUESTION I WANT TO ADDRESS IS VICA VERSA, IS THIS TRAPPING OF RECEPTORS IMPORTANT FOR LONG-TERM PLACE IS TEE AND PHASE OF LONG-TERM PLACE IS TEE. SO INITIALLY WE COULD NEVER DO THAT BECAUSE MOST OF OUR FIRST WORK WAS DONE INSIDE CULTS. AND SO WE HAD TO WAIT TO GET TOOLS TO BE ABLE TO REGULATE IN SLICES TO BE ABLE TO REGULATE RECEPTORRABILITY. SO THESE ARE FIRST SLICES OF HIP POECAMPUS. YOU SEE VERY TYPICAL SHARP INCREASE IN THE AMPITUDE. THEN WE USE THE TOOLS THAT I PRESENTED YOU EARLIER USING BIO TEEN RECEPTORS THAT WE CAN MOBILIZE TO THE CONTRIBUTION OF MOBILITY TO THIS PROCESS. SO BASICALLY WHAT WE ARE GOING TO DO IS PLAY WITH THOSE PATHWAYS, BLOCKING EITHER MOBILITY OF PRE-EXISTING RECEPTORS OR BLOBBING SYTOSIS TO THE RECEPTORS. THEN WASHOUT AND TRIGGER FTP. WHEN IT WAS FIRST EXTREMELY PLEASED, IT WAS ACTUALLY COMPLETELY WIPES OUT THIS EARLY PHASE BUT THEN WHAT HE FOUND IS THAT IT YOU WAIT A BIT, TO CREEP UP AND THAT YOU ACTUALLY REACH AFTER 30 MINUTES A LEVEL THAT'S NOT VERY FAR FROM THE CONTROL LEVEL AND SO THEY PUT THIS GAME OF -- THAT MIGHT BE DUE TO RECEPTORS, WE FUSE NORMALLY BECAUSE THERE'S MORE, SO TO CHECK THAT WE FIRST DECIDED TO BLOCK DIRECTLY, THIS IS ONE OF THE WAYS WE USED THE TOXIN TO BLOCK. REPRODUCING ACTUALLY EARLIER WORK 20 YEARS AGO FINDING THAT WHEN YOU DO THAT, YOU HAVE JUST LEFT THE INITIAL PHASE WHICH WAS INITIAL THOUGHT TO BE DUE TO PRE SYNAPTIC BUT OBVIOUSLY DUE TO RECEPTOR MOVEMENT. AND THEN WHEN YOU PRE INCUBATE YOUR SLICES TO BLOCK, YOU COMPLETELY WIPE OUT BOTH THE EARLY PHASE AND THE LATE PHASE. SO THIS WAS REALLY SHOWING THAT INITIAL PHASE HERE IS JUST TO TRAPPING OF PRE DISTRICTING SURFACE RECEPTORS THAT COME FROM AFTER -- SO THIS IS SLICES, THE REVIEWERS OF TIS PAPER ASKED US TO GO FURTHER AND SEE THE SAME THING IN ACCURATE SLICES. WAS ABLE TO COME BACK WITH SLICES AND INFUSE -- SO THIS IS SUCH AN EXPERIMENT NOW. AND YOU SEE THAT WHEN YOU DO THAT WITH CONTINUOUS PRESENCE, YOU WIPE OUT LTP. IS THAT ALSO TRUE IN VIVEO? YES. WE COULD FIND THE SAME RESULTS. BY INJECTING THESE AND EITHER THE FRAGMENT THAT'S NOT EXPECTED TO CROSS IN THOSE PICTURES IRRELEVANT IGGs. AND YOU SEE THAT ONLY IT ACTUALLY ABLE TO BLOCK LTP. WITH THOSE TUBES IN HAND, WE ARE ACTUALLY PRETTY HAPPY BECAUSE THAT MEANS WE CAN STOP ASKING FURTHER QUESTIONS IN PARTICULAR BEHAVIOR TO SEE WHETHER, WHEN DO WE BLOCK IT AND WHEN DO WE BLOCK SURFACE MOBILITY OF THE RECEPTORS CAN WE ACTUALLY BLOCK DIFFERENT FORMS OF MEMORY. SO WE'VE ACTUALLY STARTED THAT BY LOOKING AT SOMETHING EASY, FEAR CONDITIONING. BY DOING FEAR CONDITIONING, INJECTING THEM EITHER WITH FRAGMENTS OF AN TECH WITS CONDITIONING THEM TASK BY CHANGING THE ENVIRONMENT. SO THE FIRST PHASE THEY DON'T FREEZE IN THE CAGE AND THEN INJECTING THEM WITH THE INTICK WIT. AND THEN 24 HOURS LATER. THEY ARE FREEZING IN THE SAME ENVIRONMENT AND YOU SEE THAT WITH MOBILIZE THE RECEPTORS ARE INJECTED. MUCH LESS THAN THEY WOULD DO IN CONTROL CONDITIONS OF INJECTIONS. THIS IS NOT THE HYPE POECAMPUS. MANY WAYS TO TEST THAT. FIRST IF YOU PUT THE VERY SAME ANIMALS IN ANOTHER CONTEXT IN WHICH THEY HAVE NOT CONDITIONED, THEY DON'T FREEZE AT ALL. SO THEY BEHAVE NORMALLY AND THEN YOU CAN RECONDITION THEM IF YOU WAIT ANOTHER TWO, THREE DAYS, AND YOU CAN RECONDITION THEM IN YOUR CONTEXT AND THIS TIME ALL OF THE ANIMALS GET CONDITIONED NORMALLY. SO THIS WAS REALLY OF THE RECEPTORS. FINALLY IF WE DO THE SAME HERE, THEN TEST FOR NON-HYPE -- HIPPOCAMPUS. YOU SEE THAT NOW WHICH IS ALL ACUTE FEAR. SO I'M FINISHED NOW. JUST GOING TO CONCLUDE WITH A COUPLE SUMMARY SLIDES. FIRST OF ALL, IN TERMS OF ORGANIZATION IN THE RECEPTORS, I THINK THERE IS REALLY GOOD EVIDENCE FOR MANY LAPS NOW THAT EMPIRE RECEPTORS HAVE THIS VERY PECULIAR DISTRIBUTION MEMBRANE, AT LEAST IN THE SYNAPSES. ABOUT HALF OF THEM ARE CLOSE TO IT. PROBABLE THROUGH. INDICATES THAT WE HAVE NO IDEA OF WHAT KEEPS THOSE CLUSTERS TOGETHER. THERE'S SOME EVIDENCE NOW THAT THOSE ARE INDEED LAYING IN FRONT. THERE WAS A VERY RECENT PAPER BY THE GROUP THAT SHOWED THE NICE ASSIGNMENT BETWEEN MACHINERY SUCH AS REAM SO THAT'S REALLY A VERY INTERESTING THAT YOU HAVE THIS NOTION OF A NANO COLUMN TOGETHER LINKED BETWEEN THEM THROUGH ADDITION PROTEINS AND WE START TO HAVE IDEAS OF WHICH PROTEINS COULD LEAN THE SIDE, AND THEN IN BETWEEN THE RECEPTORS ARE EXTREMELY MOBILE AND REGULATION OF THE MOBILITY OF THE RECEPTORS IS IMPORTANT TO CHOSE SHORT-TERM PLASTICITY. WE ARE TRAINED TO RECONCILE THE PROPONENTS AS ALWAYS WE THINK THAT BOTH ARE IMPORTANT. WE THINK THAT THE EARLY PHASE OF SYNAPTIC PRONUNCIATION IS DUE TO TRAPPING PREEXISTING RECEPTORS THAT ARE CAN COME IN VERY QUICKLY AND THEN A BIT LATER ON RECEPTORS TAKES A WHILE FOR THOSE RECEPTORS TO COME AND REGULATE ACTUALLY THE NUMBER OF RECEPTORS OVERALL IN THE SPINE HEAD OF THE PERCENTAGE. AND WE THINK THAT'S ACTUALLY EXTREMELY IMPORTANT TO EXPLAIN WHY, FOR EXAMPLE, THE SHORTENED PLACE IS TEE OF SYNAPSES AFTER NOT SO DIFFERENT FROM THE ONE BEFORE, JUST BEFORE BECAUSE ACTUALLY YOU'VE RECOVERED THE SAME AMOUNT OF MOBILE RECEPTORS. AND WITH THIS, I'M DONE. I THANK YOU VERY MUCH. I DON'T THINK TO GO THROUGH THESE MESSAGE. I THINKING THEM PRETTY CLEARLILY. I THANK MOST OF THE PEOPLE. I WANT TO THANK THAT PROVIDES US WITH THIS ANTI-BODY, THANK YOU VERY MUCH. I'D BE HAPPY TO TAKE QUESTIONS.