>> GOOD AFTERNOON. IT'S MY GREAT PLEASURE TO INTRODUCE TODAY'S NIH DIRECTOR SEMINAR SPEAKER DR. ZHENG LI, WHO IS THE CHIEF DEVELOPMENT IN PLASTICITY IN BRAIN DISORDERS AT THE NIMH. DR. LI RECEIVED HER Ph.D. FROM THE STATE OF NEW YORK OF STONY BROOK, SHE WORKED ON ROGUE GTP As IN DENDRITE MORPH O GENESIS ON HER Ph.D. AND OBTAINED A POST DOC IN SYNAPTIC PLASTICITY AT MIT BEFORE JOINING NIH AS A TENURED TRACK INVESTIGATOR ABOUT 10 YEARS AGO. SHE'S BEEN INTERESTED IN SYNAPSE DEVELOPMENT AND SYNAPTIC PLASTICITY AND MORE RECENTLY, I THINK IN THE ROLE OF MITOCHONDRIA IN MODULULATING AND EFFECTING THESE PROCESSES AND HER TALK TODAY IS ENTITLED: MULTIFACET FACETTED SYNAPSE IT IS IN MITOCHONDRIAL SYNAPSES. DR. LI? >> WELL FIRST OFF I WOULD LIKE TO THANK DR. MICHAEL GOTTESMAN AND THE OFFICE FOR INVITING ME, GIVING ME THIS OPPORTUNITY. AND ALSO I REALLY LIKE TO THANK MY BRANCH CHIEF KAREN BERMAN AND SUSAN FOR HELPING ME THROUGH THIS ENTIRE PROCESS, WHICH IS NOT EASY. IT'S REALLY FANTASTIC THAT I HAVE THEIR SUPPORT. OKAY, SO, THE FUNDAMENTAL QUESTION THAT IS DRIVING MY RESEARCH IS TO UNDERSTAND HOW THE BRAIN CAN FULFILL THE COMPLICATED COGNITION EMOTION AND BEHAVIOR. BECAUSE OF THESE FUNCTIONS WE HUMAN CAN TALK TO EACH OTHER AND WE CAN MAKE DECISIONS AND ENJOY THE JOY OF LIFE. IF THE BRAIN DOESN'T FUNCTION WELL, VARIOUS PROBLEMS CAN ARISE AND NEUROPSYCHIATRIC DISORDERS SUCH AS DEPRESSION, SCHIZOPHRENIA IS ONE OF THE CONSEQUENCES OF BRAIN DYSFUNCTION. THE INSTITUTE OF HEALTH MATRIX AND EVALUATION REPORT THAD MENTAL DISORDER IS THE NUMBER SIX DESCREEZ WHICH CAUSE LOTS OF LIFE YEARS DUE TO DISABILITY. AND IT WAS NOTED THAT FROM 1990 TO 2015, THE DISABILITY CAUSED BY MENTAL DISORDER HAS INCREASED ALMOST TO 60%. SO MENTAL DISORDER IS REALLY A GREAT CHALLENGE FOR PUBLIC HEALTHS. THAT'S THE REASON THAT WE'RE INTERESTED IN THE MECHANISM OF MENTAL DISORDERS AND THE WAY WE TACKLE THIS QUESTION IS TO STUDY NEURONS. IN PARTICULAR, SYNAPSES IN NEURONS. SO, SYNAPSES ARE THE SPECIALIZED THE COMPACT SIZE BETWEEN PRESIN APTING NEURON AND THE POST SIN APTING NEURON. A CHEMICAL SYNAPSE IN THE BRAIN IS COMPOSED OF A PRESENTED SIDE WHICH HAS NEUROSYNAPTIC VESICLES CONTAINING TRANSMITTERS AND POST SIDE, WHICH HAS NEUROTRANSMITTERS AND VARIOUS SIGNALING MOLECULES. WHEN THE PRESYNAPTIC NEURON FIRES ACTION POTENTIALS, SYNAPTIC VESICLES WILL BE RELEASED FROM THE PRESYNAPTIC SIDES AND WILL BIND TO RECEPTORS AT POST SYNAPTIC SIDE TO ACTIVATE POST SYNAPTIC NEURON. THE SIN APTSIS IN THE BRAIN CAN BE DIVIDED AND CLASSIFIED INTO THE SYNAPSES AND INHIBITOR SYNAPSES, THE MAJORIT OF SYNAPSES IN THE BRAIN ARE FOUND ON THESE DENDRITIC CELL RIDDIC SPINES WHICH ARE TINY PROTRUSIONSOT DENDRITIC SHORT. SO ALL WORK HAS EXCITATORY SYNAPSES AND SO, THE MAIN FUNCTION OF SYNAPSES IS TO TRANSMIT INFORMATION BETWEEN NEURONS AND THE STRENGTH OF THIS INFORMATION CAN BE MODULATED BY NEUROONAL ACTIVITIES. THIS PROCESS IS CALLED SYNAPTIC PLASTICITY. IN THIS PLASTICITY, THE STRESS CAN BE POTENTIATED OR DEPRESSED. AND WHEN THE SYNAPTIC STRENGTH HAS CHANGED, OFTEN THE DENDRITIC CELL RIDDIC SPINE CHANGE, AND SO THIS POTENTIATION IS SOCIALITIED WITH THE POETIC TEBTIATION. AND THE DENDRITIC SPINE IS LARGELY ASSOCIATED WITH THE POTENTIATION AND THE SPINE ELIMINATION AND SPINE SHRINKAGE IS ASSOCIATED WITH SYNAPTIC DEPRESSION. SO, IN OUR LAB, WE'RE INTERESTED IN THE MOLECULAR MECHANISMS UNDERLYING SYNAPSE DEVELOPMENT AND PLASTICITY AND WE'RE AWLINGS INTERESTED IN THE MECHANISMS IN MORPHOLOGY OBSERVED IN NEUROPSYCHIATRIC DISORDERS. SO TODAY, I WILL TALK ABOUT ONE OF THE ALIGNED RESEARCH WE HAVE DONE IN THE LAST 10 YEARS ALSO WHICH IS CONCERNING THE FUNCTION OF THE MITOCHONDRIA IN SYNAPSES. WE KNOW THAT MITOCHONDRIA, FROM THE UCARIOTIC CELLS. THEY ARE ALSO CALLED CELLULAR POWER PLANT BECAUSE THEY PRODUCE 90% CELLULAR ATP. THEY ALSO REGULATE INTRA CELLULAR CALCIUM AND PARTICIPATE IF POPITOSEIS. SO MITOCHONDRIA ARE IMPORTANT FOR SELF-PHYSIOLOGY. WE KNOW THIS BECAUSE WHEN THE GENES ENCODING--ENCODING MITOCHONDRIAL PROTEINS ARE MUTATED, IT OFTEN LEADS TO MITOCHONDRIAL DISEASES. THIS IS A PATTERN OF DISEASES THAT HAVE EFFECTED MULTIPLE ORGANS AND MOST OF THE PEOPLE WITH MITOCHONDRIA DISEASES HAVE A NEUROLOGICAL AND PSYCHIATRIC MANIFESTATIONS. ON THE OTHER HAND WE OFTEN OBSERVE THE CHANGE IN MITOCHONDRIAL FUNCTION AND BRAINS OF PEOPLE EFFECTED BY BRAIN DISORDERS. SO THIS ACTIVATION SUGGESTS THAT THERE IS A CLOSE RELATIONSHIP BETWEEN MITOCHONDRIA OF PATHOLOGY AND BRING DISORDERS SO THIS IS NOT SURPRISING GIVEN THE MITOCHONDRIA FOR SYNAPSES IN THE BRAIN FUNCTION. BUT, BUT BASED ON OUR WORK AND A NUMBER OF OTHER GROUPS WE NOW KNOW THAT NEURONS HAVE MORE SPECIFIC FUNCTIONS WHICH MAKE THEM OF SPECIAL EXPERIENCE FOR NEURONS SO THIS IS THE OUTLINE I'M GOING TO TALK ABOUT TODAY. SO FIRST OFF I WILL TALK ABOUT HOW MITOCHONDRIA SYNAPSE DEVELOPMENT AND ACTIVITY INDUCED SPINE ENLARGEMENT AND SOME OF OUR UNPUBLISHED WORK ON THE FUNCTION OF THE MITOCHONDRIA, PATHOLOGY SOCIALED WITH SCHIZOPHRENIA. AND LASTLY I WILL TOUCH UPON MIELT O CHOND RIA LONG-TERM DEPRESSION OR LTD. >> THIS IS A PICTURE OF HIPPO CAMPO NEURON. IN THIS NEURON, THIS IS LABELED WITH THE FLUORESCENT PROTEINS. YOU CAN SEE THAT THE MITOCHONDRIA EXISTS AS VARIABLE SIZES AND SHAPES. THEY HAVE A HIGH DENSITY CELL BODY AND EXTEND THROUGHOUT NEURONAL DEPPED RIGHTS AND AXONS. MITOCHONDRIAL ARE DYNAMIC STRUCTURES MEANING THEY MOVE AROUND BUT THEY ALSO CONSTANTLY CHANGE THEIR NUMBER AND SHAPE SO MITOCHONDRIA EFFICIENT AND EFFUSION. SO A NUMBER OF YEARS AGO WHEN I WAS A POST DOCTORAL FELLOW. I FOUND THAT ALTHOUGH THE MAJORITY OF MITOCHONDRIA ARE IN THE DENDRITIC SHOP, THERE ARE A SMALL NUMBER CAN BE FOUND IN THE DENDRITIC DENDRITIC SPINES. SO FOR EXAMPLE, THIS IS A PIECE OF DENDRITE FROM THE HIPPOCAMPAL NEURON AND HERE IS THE HEART OF THE SPINE. IN THE HEART OF THE SPINE THERE IS MITOCHONDRIA AND ALTHOUGH A NUMBER OF SPINES IS LOW, THE COUNT IS LOW. WHEN NEURONS ARE STIMULATED, MITOCHONDRIA CAN TRANSLOCATE TO DENDRITIC SPINES. WE FOUND WHEN WE DID A LOCAL STIMULATION EXPERIMENT IN HIPPOCAMPAL SLICES, SO THIS IS DENDRITE FROM THE HIPPOCAMPAL NEURON WHICH IS LABELED WITH THE FLUORESCENT PROTEINS AND THIS IS A STIMULATED ELECTRON, WE APPLY THIS IN A WAY THAT WE ONLY STIMULATE THE ELECTRODE CLOSE TO THE ELECTRODE. WE KNOW THE STIMULATION IS LOCAL BECAUSE WE USE EYE FERENCEQUENCE--HIGH FREQUENCY STIMULATION. IN THE DENDRITE CLOSE TO THE ELECTRODE, WE OBSERVE THE SPINE ENLARGEMENT BUT IN THE SEGMENT, FROM THE ELECTRODE, THERE'S NO CHANGE IN STYLE MORPHOLOGY. AND IN THIS DENDRITE MITOCHONDRIA AFTER STIMULATION TRANSLOCATE INTO THE LARGE DENDRITIC SPINE. THIS IS NOT OBSERVED IN THE UNSTIMMULATED DEPPED RIGHT. WE FURTHER FOUND THAT THIS MITOCHONDRIAL LOCATION IS POST SYNAPTIC MUTATION. SO HERE WE'RE LOOKING AT A NUMBER OF PROTRUSIONS CONTAINING MITOCHONDRIA IS INCREASED BY EXCITATION, BUT IT WILL BLOCK NMD DEREPRESENTORS WITH ATP FIVE AND WE CAN BLOCK THESE ACTIVITY INDUCED MITOCHONDRIAL TRANSLOCATION. SO WHY DID THEY TRANSLOCATE INTO THE SPINES? SO WE WENT--THESE SPINES ARE UNDERGOING MORPH LOGICAL CHANGE. SO MITOCHONDRIA MIELT BE RELATED TO THE CHANGE OF THE DENDRITIC DENDRITIC SPINES. AND THIS INDEED CONSIST WENT TWO OTHER OBSERVATIONS WE HAVE MADE IN THE SAME TYPE OF NEURONS. SO FIRST OFF WHEN THEY LOOK AT THIS, WHICH ARE LESS THAN TWO WEEKS OF AGE, WHEN THEY ARE ACTIVELY GROWING SPINES AND SYNAPSES, WE FOUND THAT THERE ARE A LOT MORE DENDRITIC SPINES CONTAINS MITOCHONDRIA THAN IN MORE MATERIAL NEURONS. AND THE SECOND WAY WE FOUND THAT IS WHEN WE DIRECTLY CHANGE IN DENDRITES WE CAN ALTER THE NUMBER OF SPINES IN THE SYNAPSES. SO WE DO THIS BY USING THE DRP-ONE PROTEIN, IT'S A DIAMEAN RELATED GTPACE. IT'S A MITOCHONDRIA EFFICIENT, AND ALSO IT CAN PROMOTE THE DISTRIBUTION OF MITOCHONDRIA IN DENDRITES. WHEN WE EXPRESS THE DRP-ONE, THE MUTANT IN HIPPOCAMPAL NEURONS WE DECREASE THEIR NUMBER OR TOTAL AMOUNT OF MITOCHONDRIA IN DENDRITE. WHEN WE EXPRESS WILD TYPE DRP-ONE IN DENDRITE WE INCREASE THE AMOUNT OF MIGHT MITOCHONDRIA IN THE DENDRITE. AND AT THE SAME TIME WE FOUND A CHANGE IN THE DENDRITIC SPINE AND SYNAPSES. SO HERE WE CAUGHT A SPINE NUMBER AND HERE WE LABEL THE SYNAPSES USING THE DYE AND WHICH LABELS SO DRPONE WHICH INCREASE THE NUMBER OF SPINES IN THE SYNAPSES AND WILD TYPE DRP ONE WHICH INCREASE AND CAUSE INCREASES IN SPINE NUMBER AND SYNAPSE DENSITY. SO THESE RESULTS INDICATE THAT THE AMOUNT OF MITOCHONDRIA IN DENDRITE DETERMINES THE NUMBER OF SYNAPSE IT IS AND DENDRITIC SPINES. AFTER I JOIN NIH, I STARTED TO BECOME INTERESTED IN THE MECHANISM OF SIN APTSIC PATHOLOGY ASSOCIATED WITH MENTAL DISORDERS, IN PARTICULAR, I HAVE BEEN WORKING ON THE SYNAPTIC MORPHOLOGY OF SCHIZOPHRENIA. SO I FIRST A QUICK INTRODUCTION OF SCHIZOPHRENIA. WE KNOW IT'S A SERIOUS MENTAL DISORDER, IT HAS 1 PERCENT OF PREVALENCE IN THE POPULATION WORLD WIDE. IT'S A DEBILITATING DISORDER, IT'S AMONG TOP 10 DISEASES WHICH CAUSE LARGEST FINANCIAL BURDEN. THE TYPICAL AGE OF ONSET FOR SCHIZOPHRENIA IS LATE ADOLESCENCE OR EARLY ADULTHOOD. THE PATIENTS HAVE A WIDE RANGE OF SYMPTOMS INCLUDING PASSIVE SYSTEMS SUCH AS NEGATIVE DELIEWGDZS, HALLUCIATIONS DISORGANIZE TD THOUGHTS AND IMCOGNITIVE IMPAIRM. THE MAIN STREAM MEDICATION IS ANTIPSYCHOTICS AND THOSE HAVE BEEN USED FOR DECADES BUT STILL THERE ARE ABOUT 20-50% OF PATIENTS DO NOT RESPOND TO ANTIPSYCHOTICS, AND AMONG THOSE THOO DO RESPOND 50% OF THOME ONLY OBTAIN PARTIAL IMPROVEMENT. COGNITIVE IMPAIRMENT WHICH IS A CORE SYMPTOM OF SCHIZOPHRENIA, ANTIPSYCHOTICS HAVE VERY LITTLE EFFECT. SO THIS IS A STRONG NEED TO TODAY THE MECHANISM OF SCHIZOPHRENIA TO DEVELOP EITHER TREATMENT. SO, OVER THE YEARS WE HAVE--WE KNOW THAT THE MENTAL--SCHIZOPHRENIA IS CAUSED BY COMBINATION OF GENETIC AND ENVIRONMENTAL FACTORS. SO FOR EXAMPLE, IN THE STUDY, IT FOUND THAT THE IDENTICAL QUIZ OF 50% PATIENTS HAVE 50% OF DEVELOPING SCHIZOPHRENIA. AND THEN A GENETIC STUDY VS IDENTIFIED MANY SCHIZOPHRENIA RISK GENES. SO THERE ARE MANY EVIDENCE, POINTING THAT THERE ARE INDEED SYNAPTIC SPIKES IN THE SCHIZOPHRENIA. FOR EXAMPLE, IN THE POSTMORTEM BRAINS OF SCHIZOPHRENIA PATIENTS, NEURONS HAVE SPINES CO COMPARE TO CONTROL, WHICH SUGGIEST THAT THE SYNAPSE NUMBER IS REDUCED. THE SECOND LEVEL EVIDENCE COMES FROM MEDICATIONS. SO ALL CURRENT ANTIPSYCHOTICS ARE BLOCKERS FOR THOSE MD RECEPTORS AND THE EFFICACYS CORRELATE WITH THEIR CASE WITH THE RECEPTORS ON THE OTHER HAND AMPET MINE WHICH CAN INCREASE DOPA MINE LEVELS CAN CAUSE INDUCED PSYCHOSIS. SO A NEW MODULATOR, DOPA MINE SYSTEMS AND DTWO RECEPTORS APPEAR TO BE CLOSELY RELATED TO THE PSYCHOPATHOLOGY OF SCHIZOPHRENIA.MORE RECENTLY, THE NUMBER OF VARIANCE AND MUTATIONS IN SCHIZOPHRENIA PATIENTS ARE ENRICHED FOR GENES THAT ENCODE POST SYNAPTIC SIGNALING COMPLEXES AGAIN, SUGGESTING THAT SYNAPTIC PATHOLOGY PLAY AN IMPORTANT ROLE IN SCHIZOPHRENIA. SO WE DECIDED TO LOOK FOR MECHANISM FOR PATHOLOGY AND WE DECIDED TO TAKE A CANDIDATE APPROACH. WE SELECTED TO STUDY DTNBP1. THIS IS A FIRST UP BECAUSE IT'S A SCHIZOPHRENIA RISK GENE. IT WAS FIRST REPORTED BY RICHARD STRAUB, THAT 2002, THAT THIS GENETIC VARIANT WAS ASSOCIATE WIDE THIS GENE FOR INCREASED RISK FOR SCHIZOPHRENIA. AND THIS SLIDE HAS BEEN REPLICATED BY MANY OTHER GROUPS LATER ON. SO DTNBP1 IS TO ENCODE THE BINDING PROTEIN OR DYSBINDIN FOR SHORT. THIS IS INCREASED IN THE DORSAL LATERAL FREE RADICALS FRONTAL CORTEX OF SCHIZOPHRENIA PATIENTS. DISBINDIN IS A COMPONENT OF THE BLOC-1 COMPLEX. THIS COMPLEX IS COMPRISED OF 8 SUBUNITS. YOU KNOW IN ADDITION TO THE THIS FINDING, BLOCK 1 AND S3 ARE MUTED AND ALSO GENETICALLY ASSOCIATED WITH SCHIZOPHRENIA. AGAIN SUGGESTING THAT THIS COMPLEX MAY BE RELATED TO SCHIZOPHRENIA. SO IN HUMANS THIS FINDING AS 3 SLICING ISOFORMS, 18, 1 B AND 1 C, IN MUTANTS THERE ARE ONLY 2 ISOFORMS AND THESE 2 ISOFORMS ARE DEVELOPMENTALLY REGULATED. ONE IT DECREASES WITH THE AGE AND ONCE IT INCREASES WITH AGE. SO SINCE THIS FINDING WAS DISCOVERED, MANY PEOPLE HAVE A LOOK AT THE FUNCTION OR THIS BINDING. NOW WE KNOW THAT THE BINDING HAS MULTIPLE FUNCTIONS IN NEURONS SO FOR EXAMPLE, IT CAN REGULATE SURFACE EXPRESSION OF THE DOPA MINE RECEPTORS AND THE RECEPTOR AND ALSO INVOLVED IN THE VESICLE RELEASE AND THE SYNAPTIC PLASTICITY. SO TO TEST WHETHER THIS BINDING IS INVOLVED IN OR HAS ANYTHING TO DO WITH THE SPINES. WE LOOK AT SPINES IN THE MUTANT MICE. THESE MICE CARRY SPONTANEOUS DELETION IN THE DTMB 1 GENE WHICH LEADS TO THE ABSENCE OF THE PROTEIN IN THE MICE. THE MICE, THIS IS--THIS IS THE KNOCK OUT MICE IS GROSSLY NORMAL COMPARED TO THE WILD TYPE MICE. THE MOST OBVIOUS PHENOTYPE OF THE MICE IS THAT THEIR FUR COLOR HAS A SAND LIKE COLOR, THAT'S WHY THEY ARE CALLED THE SANDY MICE. WE INJECT THE LEBTY--ULENTY VIRALS EXPRESSING GFP TO LOOK AT THE DENDRITIC CELL RIDDIC SPINES SO THESE ARE THE DENDRITES AND YOU CAN SEE SPINES ON THE DENDRITE IS SHOT. COMPARED TO WILD TYPE MICE, WE KNOW THAT SANDY MICE HAVE LOWER OR FEWER THAN DENDRITIC SPINES. AND IT'S MORE INTERESTING THAT THIS SPINE DEFICIT IS ONLY OBSERVED IN MICE WHICH IS DURING THEIR ADOLESCENT AGE. THIS IS IN THE MICE, IF WE LOOK AT YOUNGER OR OLDER MICE, THE SPINE NUMBER IS A COMPARABLE FOR THE MICE. THIS FINDING IS INCREEINGING BECAUSE WE KNOW ADLEASE ENSEL IS THE--ADOLESCENCE IS WITH THE FUNCTION OF THE REGULATING DENDRITIC DENDRITIC SPINES MAY CONTRIBUTE TO THE DEVELOPMENT OF SCHIZOPHRENIA. WE WANT TO KNOW HOW THEY REGULATE THE SPINES SO I WILL CUT--I WILL MAKE IT SHORT. SO IT TURNS OUT THAT THIS IS BECAUSE THE BINDING CAN REGULATE SURFACE EXPRESSION OF THE D-2 RECEPTORS, INCENTIVIZE THE MORE RECEPTORS, SO D2 RECEPTORS ARE ALL ACTIVATED AND AS A RESULT OF THAT, THE SPINE MATURATION IS INHIBITED SO THERE ARE FEWER THAN THE SPINES IN THE SANDY MICE. WE CAN RESCUE THE SPINE DEFICIT USING LOXAPINE, IT IS AN ANTIPSYCHOTIC AND HAS A HIGH AFFINITY FOR D2 RECEPTORS WE ALSO TESTED CLOZAPINE BUT IT HAS A WEAK AFFINITY FOR D-2 RECEPTORS. AGAIN SUGGESTING THAT D2 RECEPTORS, ACTIVATION IS IMPORTANT FOR THIS PHENOTYPE. SO ALTHOUGH THIS NUMBER IS LOWER, IT'S DURING THE ADOLESCENCE BUT IN ADULTS THE SANDY MICE MANAGE TO GROW ENOUGH SPINES SO THAT THE NUMBER IS THE SAME AS IN WILD TYPE MICE. BUT HOWEVER, WE FOUND THAT BECAUSE ADOLESCENCE IS A PERIOD WHEN CREE IS NOT FULLY MATURE, THE SYNAPTIC CONNECTIVITY ARE STILL UNDERGOING A LOT OF REFINEMENT AND REARRANGEMENT AND PROCESS TO OBTAIN THE PRESETS CONNECTIVITY AS THE ADULT MOUSE BRING. SO THE TEMPLATE PROTURB AWGZ OF SPINE DEVELOPMENT IN THE SANDY MICE DURING ADOLESCENCE ACTUALLY LEAD TO PERMANENT IMPAIRMENT OF SYNAPSE CONNECTIITY AND BEHAVIOR WHICH CAN NOT SEEM TO DOUBLED. SO FOR INSTANCE WE LOOK THE CORTEX AND THE HIPPO CAMPUS. SO THE LAT LEAST NEURONS IN THE CORTEX AND THE MONOSYNAPTIC CONNECTION TO THE C1 REGION OF HIPPO CAMPUS. WE INJECTED THE CTP INTO THE CE-1 REGION TO GRADUALLY LABEL THE CORTICAL NEURONS PROJECT TO THE CE REGION. AND THE RED CELLS HERE ARE THE LABELED CELLS. SO IN WILD TYPE WE CAN SEE THAT THE LABELED NEURONS ARE DISTRIBUTED ALMOST EVENLY ACROSS THIS MEDIAL LATERAL ACCESS OF INTERRHINAL CORTEX, BUT IN SANDY MICE, THE DISTRIBUTION OF THESE CELLS IS SHIFTED LATERALLY. AND AGAIN THIS IS FROM D2 ACCEPTOR, WE CAN PRESHAPE THE CONNECTIVITY FROM HAPPENING BY USING D2 RECEPTOR ANTAGONIST IN THE SANDY MICE DURING ADOLESCENCE BUT IF WE BLOCK D-2 RECEPTORS IN ADULT MICE WHEN [INDISCERNIBLE] HAS HAPPENED. IT'S TOO LATE. WE CANNOT CANNOT--WE CANNOT CORRECT THIS DEFECT ANYMORE. SO THE INTERRHINAL CORTICAL CONNECTION IS A RESULT OF THIS MISFIRING IN THE PATHWAY. THE MOUSE DISPLAYED IMPAIRMENT IN SPACIAL WORKING MEMORY. WHEN WE TESTED IN 1 MAZE WHICH IS A TEST BEFORE THE WORKING MEMORY WE FOUND THAT THE SANDY MICE HAVE A LOWER AUTOMATION SCORE. INDICATING THAT I HAVE POOR WORKING MEMORY, BUT WE CAN CORRECT THIS DEFECT BY USING D2 RECEPTOR BLOCKERS DURING ADOLESCENCE BUT WE CANNOT DO THIS, WE CANNOT CORRECT THIS ANYMORE WHEN THE ANIMAL REACHED ADULTHOOD. SO THESE FINDINGS INDICATE THAT BY REGULATING SPINE MATURATION DURING ADOLESCENCE, THIS FINDING CONTRIBUTED TO THE MATURATION AND DEVELOPMENT OF THE BRAIN CIRCUIT AND THE DEVELOPMENT OF THE BEHAVIOR. AND ALSO, THEY SUGGEST THAT MAYBE THE COGNITIVE IMPAIRMENT IN THE SCHIZOPHRENIA PATIENTS HAVE DEVELOPED WELL BEFORE THE MANIFESTATION OF OTHER SYMPTOMS SUCH AS PSYCHOSIS AND THERE'S A KREDICATE TOWARD THAT THE INTERVENTION HAS TO BE ADMINISTERED TO PREVENT THESE COGNITIVE IMPAIRMENT. SO I HAVEN'T TALKED ABOUT MITOCHONDRIA SO FAR, BUT I WILL MOVE ABOUT MITOCHONDRIA INCENTIVIZE, SO AFTER WE FIND THIS TAP, WE LOOK AT THE INCENTIVIZE MORE CAREFULLY BECAUSE BLOCK 1 COMPROMISE HAS BEEN INDICATED IN THE FORMATION OF SOME OLIGMERS, SO WE'RE KEERIOUS ABOUT THE ORGANLES IN THE MICE HAVE CHANGED AND WE LOOK AT MANY ORGANLES AND LIES STUDIES OF MULTIPLE ENDOCRINE AND MANY OTHERS AND THE MOST STRIKING FINDING WE HAVE IS MITOCHONDRIA IN THE SANDY MICE ARE DIFFERENT. SO THESE ARE FROM THE HIPPO CAMPUS, WHICH THEY ARE LABELED WITH THE PROTEIN. SO 1 CAN SEE THAT MITOCHONDRIA,A PEER TO BE LONGER IN THE SANDY MICE. WE WERE VERY EXCITED ABOUT THIS FINDING BECAUSE BASED ON OUR WORK WE KNOW THAT MITOCHONDRIA ARE SO IMPORTANT FOR THE NEURONS AND SYNAPSES, SO THEN WE WANT TO FOLLOW THIS FINDING SO FOR EXAMPLE, WE WANT TO KNOW, WHY MITOCHONDRIA ARE ELONGATED IN SANDY MICE. SO MITOCHONDRIA LENS IS DETERMINED BY MITOCHONDRIA FUSION AND EFFICIENT. THESE ARE THE 2 DYNAMIC PROCESSES REGULATED BY DIFFERENT SETS OF PROTEINS. FISSION IS REGULATED BY PROTEIN SLIDE, AND MF, AND MANY OTHER PROTEINS. SO THEN WE DECIDE TO LOOK AT AND MEASURE MITOCHONDRIA INFUSION. AND THE WAY WE DID THAT IS WE TOOK IMAGES IN THE HIPPOCAMPAL NEURONS AND THEN WE CAN DETECT FISSION AND EFFUSION. SO THESE ARE THE IMAGES, THE RED ARROWS INDICATE THE MITOCHONDRIAL EFFICIENT SITE AND THE YELLOW AREAS POINT TO THE FUSION SITE. ONE CAN SEE THAT IN SO MANY SLICES THERE ARE FEWER ARROWS INDICATING THAT THERE ARE FEWER MITOCHONDRIA FUSION BENDS. SO MITOCHONDRIA FUSION IS THE SAME AS IN THE WILD TYPE MICE. SO THE ELONGATION IN THE SANDY MICE IS DUE TO REDUCTION IN MITOCHONDRIA FISSION. SO THE PREVIOUS WORK SHOW THATTED NEURONS IS IMPORTANT FOR SYNAPSE DEVELOPMENT AND THE SYNAPTIC ACTIVITY. SO THEN, NOW THAT WE FOUND THE MITOCHONDRIA PHENOFIEP, WE ARE--PHENOTYPE, WE ARE CURIOUS ABOUT THIS MITOCHONDRIA FISSION HAS A CONSEQUENCE OF SYNAPTIC FUNCTION. SO TO DO THIS, WE RECORDED FROM THE NEURONS TO THE ELECTROPHYSIOLOGICAL PROCESS AND WE LOOK AT THESE NEURONS AND THE MOST INTERESTING FINDING WE HAVE IS THAT THE SENTER NEURONS HAVE A LOWER EXCITABILITY. SO WE--FOR EXAMPLE, WHEN WE INJECTED CURRENTS WAS INCREASING INTENSITIES INTO NEURONS. WHEN THE CURRENT INTENSITY REACHES A CERTAIN LEVEL, NEURONS START TO FIRE ACTION POTENTIALS. WHEN YOU INJECT MORE CURRENTS INTO THE NEURONS TO ELIAISONSITATE ACTION POTENTIALS. INDICATING THAT SANDY NEURONS HAVE LOWER EXCITE ANLT. AND ALSO WITH THE NEURONS ARE STIMULATED WITH THE HIGH FREQUENCY STIMULATIONS, SANDY NEURONS HAS AN IMPAIRMENT IN THIS EXPERIMENT. SO HERE WE WE STIMULATED NEURONS AT DIFFERENT FREQUENCIES WHEN THE STIMULATION FREQUENCY IS BELOW CAN FOLLOW THE STIMULATION AS INDICATED BY THE ALMOST PERFECT FIRE AND PROBABILITIES. WHEN THE STIMULATION FREQUENCY IS ABOVE CIRCUITS WILD TYPE STOP TO FIRE THEIR JOB HOP, AND THIS HOP IS MUCH MORE GREAT IN THE SANDY NEURONS WHICH INDICATE THAT THE SANDY NEURONS HAVE A HARD TIME TO FOLLOW HIGH FREQUENCY STIMULATIONS. AND WE THINK THAT MAYBE NEURON, THE SANDY NEURONS DO HAVE DIFFICULTIES TO PERFORM WELL, THE NEURONS DURING THE HIGH FREQUENCY NEURAL ACTIVITIES. AND THE 1 TYPE OF NEURAL ACTIVITIES, FREQUENCIES ABOUT [INDISCERNIBLE] IS A GAMMA OSCILLATION. SO GAMMA OSCILLATION IS SYNCHRONIZED NEURAL ACTIVITIES WHICH ALSO ACETALATE TO HERTZ, THESE HAVE BEEN RECORD INDEED MUSEUM MAN AND ANIMAL BRAINS. THESE ARE THE LOCAL FIELD POTENTIALS RECORKED IN THE HUMAN SUBJECT--RECORDED IN THE HUMAN SUBJECTS AND THEN THE COLORS HERE INDICATE THE LOCAL FIELD OF THE POTENTIALS. SO WHEN THE SUBJECT IS PRESENTED WITH ALL THIS STIMULATION, OR RATIO STIMULATION THE LOCAL FOR INCREASE ESPECIALLY AT THIS GAMMA RANGE. AND IT'S INTERESTING TO KNOW THAT IN THE SCHIZOPHRENIA PATIENTS, THE SENSORY STIMULATION EVOKED LOCAL FIELD POTENTIAL IS GREATLY REDUCED AND THIS REDUCTION OF GAMMA OSCILLATION IN SCHIZOPHRENIA PATIENTS IS A START TO BE RESPONSIBLE FOR THEIR IMPAIRMENT OF A COGNITIVE FUNCTION. SO, BECAUS OF THIS IMPLICATION, THE GAMMA OSCILLATION IN SCHIZOPHRENIA, WE DECIDED TO LOOK AT GAMMA OSCILLATION IN SANDY MICE. WE INDUCE THE GAMMA OSCILLATION IN HIPPOCAMPALLAL SLICES USING CARBON CODE,. SO IT'S A AGANIST, WHEN IT'S INNERDUCED IT CAUSES ROBUST GAMMA OSCILLATION AS SHOWN BY THE SPECTRUM HERE. SO THIS IS THE COLOR, AGAIN INDICATE THE AMPLITUDE OF THE LOCAL FIELD POTENTIALS AND THIS IS THE AMPLITUDES AT DIFFERENT FREQUENCIES WITH THIS KIND. NOW THE TOPICAL TREATMENT THERE'S A BIG INCREASE IN OSCILLATION AT THE GAMMA BEND BUT IN THE SANDY SLICES, THE GAMMA OSCILLATION IS GREATLY REDUCED. AND IT TURNS OUT THAT THIS REDUCTION GAMMA OSCILLATION IS BECAUSE OF LOSS OF THE 1 C ISOFORM BUT NOT 1 A ISOFORM BECAUSE WHEN THEY EXPRESS THIS BINDING 1 C IN SANDY MICE, WE CAN ALMOST--WE CAN RESCUE THE GAMMA OSCILLATION BUT IF WE EXPRESS THE SANDY 1A WE CANNOT RESCUE GAMMA OSCILLATION. AND WE ALSO FOUND THAT IN ORDER FOR THE GAMMA OSCILLATION TO BE MAINTAINED FOR LONG PERIOD OF TIME. MITOCHONDRIA FISSION IS REQUIRED. IF WE TREATED THE SLICES WITH THE MITOCHONDRIA FISSION OR OR THE DRP1, WE CAN AWZ--CAUSE A GREAT REDUCTION OF GAMMA OSCILLATION. SO NOW WE FOUND THAT GAMMA OSCILLATION IS REDUCED AND MIELT O CHOND RIA FISSION IS REDUCED IN SANDSY MICE AND THEN WE DETERMINE WHETHER THERE'S A CAUSAL RELATIONSHIP BETWEEN THESE 2 PHENOTYPE. SO THORS DO--TO DO THIS, WE DEVELOP A LIGHT INDUCED MITOCHONDRIAL FISSION. SO THIS SYSTEM IS BASED ON THE LIGHT INDUCED IN THE COMPUTATIONAL CHANGE OF THE CRC2 PROTEIN. SO IT'S STIMULATED WITH THE BLUE LIGHT, IT'S COMP PLAIGZ WILL LEAD TO INTERACTION WITH THE PRIOR TO INTERACKING PROTEIN OR CIBM. SO WE TAKE ADVANTAGE OF THESE LIGHT-INDUCED COMPUTATIONAL AND PROTEIN INTERACTION. WE FUSED DRP1 WITH CIB1 AND CRY 2. WE TRANSPOSE THESE INTO HIPPOCAMPAL NEURONS AND WHEN WE SHED BLUE LIGHT ON THE NEURONS AND THEN WE FOUND THAT THE DRP 1, BECAUSE OF THE INTERACTION BETWEEN CIB, AND THE CRY 2, THIS IS INCREASED WHICH IS INDICATED BY THE INCREASE, THE SIZE OF THE BRP 1. AND AS A RESULT OF A BRP 1, MITOCHONDRIA EFFICIENT IS INCREASED SO WE DETECTED MORE MITOCHONDRIA AFTER THE LIGHT STIMULATION. SO THE SYSTEM WORK, NOW WE WANT TO TEST WHETHER IT CAN HAVE EFFECT ON GAMMA OSCILLATION. SO WE--USE THE VIRUS TO EXPRESS THESE PROTEINS IN SANDY NEURONS AND THIS IS--THEN WE LOOK AT TOP CO INDUCED GAMMA OSCILLATION. SO SANDY MICE HAVE BIG GAMMA OSCILLATION BUT WITH LIGHT STIMULATION, THE GAMMA OSCILLATION IS GREATLY RECOVERED AS CONIFICATION HERE SO IT'S ALMOST TO THE SAME LEVEL AS WILD TYPE MICE. IN THE CONTROL SLICES WHICH IS EXPRESSING CIB1 AND LY2 STIMULATION DOESN'T CHANGE GAMMA OSCILLATION, SO THIS RESULT SUGGESTS THAT THE INEFFICIENT MITOCHONDRIA FISSION IN THIS BINDING MUTANT IN THE MICE IS INDEED RESPONSIBLE FOR THE IMPAIRMENT OF GAMMA OSCILLATION. THE LIGHT MITOCHONDRIAL EFFICIENT IS IMPORTANT FOR GAMMA OSCILLATION. SO WE SPECULATED THAT AFTER MITOCHONDRIAL FISSION, MITOCHONDRIA BECOMES SMALLER AND SOME SMALLER MITOCHONDRIA MIGHT BE MORE MOBILE AND THEY CAN MORE EASILY MOVE TO SYNAPSES TO BETTER SUPPORT SYNAPTIC ACTIVITIES AND HIGH FREQUENCIES SO THAL TOO WOULD PREDICT THAT THIS WOULD TRANSLOCATE TO GAMMA SYNAPSES DURING THE OSCILLATION. SO WE TESTED THIS IDEA OF THE HIPPO CHAMPAL NEURONS. SO WE LABELED THIS USING THE PSD95 VENUS AND, AND WE LABELED THE MITOCHONDRIA WITH THE MITODS RED, SO WE LABELED IT BEFORE AND AFTER. SO AFTER WE SAW THE RANGE WE FOUND THAT IN THE CELLS--SO THE NUMBER OF SYNAPSES CONTAINING MITOCHONDRIA IS INCREASED SO, GAMMA OSCILLATION IS ASSOCIATED WITH MITOCHONDRIA TRANSLOCATION TO SYNAPSES. SO THIS BIND SUGGEST KNOCKED DOWN, BEFORE GAMMA STIMULATION, THERE ARE ALREADY FEWER SYNAPSES CONTAINING MITOCHONDRIA AND AFTER SIMULATION, IT DIDN'T FURTHER INCREASE THE NUMBER OF SYNAPSES CONTINUE WITH MITOCHONDRIA. SO THIS TELLS US THAT, MITOCHONDRIA TRANSLOCATE TO SYNAPSES DURING GAMMA ON OSCILLATION AND THIS TRANSLOCATION IS INDEPENDENT ON THIS BINDING. SO NOW WE FOUND THAT IN DISBANDING THE MUTANT MICE THERE ARE FEWER MITOCHONDRIA SYNAPSES SO THEN WE WONDERED WHETHER THE LACK OF MIELT O CHOND RIA CONTRIBUTES TO THE GAMMA OSCILLATION DEFECT? SO WE DESIGNED AN APPROACH TO INCREASE MITOCHONDRIA SYNAPSES, AND THE WAY WE DO THAT IS WE EXPRESS PS95 MITOCHONDRIA, PS95 IS BINDING TO POST SYNAPTIC DENSITY. SO BY TARGETING PSD95, TO MITOCHONDRIA, WE CAN INCREASE OR TARGET MIGHT MITOCHONDRIA THROUGH THE SYNAPSES. AND AS A RESULTED OF THIS, WE ALSO CAN ENHANCE GAMMA OSCILLATION IN SANDY MICE. SO, THESE RESULTS SUGGEST THAT THE REDUCTION OF MITOCHONDRIA SYNAPSES IN SANDY MICE ALSO CONTRIBUTE TO THE GAMMA OSCILLATION IMPAIRMENT. THEN THE NEXT QUESTION WE ASK IS, HOW DISBANDING REGULATES MITOCHONDRIA EFFICIENT? THIS IT TURNS OUTED THIS IS BECAUSE THE BINDING CAN BIND TOO AND PROMOTE THE OLIGMERRIZATION, SO THE DRP 1 IS A PROTEIN PRIMARILY EXISTS AS OLIGMERS IN THE CELLS. IN THE CYTOSOL, BRP 1 IS MAINLY--AS TETRAMERS OR DIMERS. WHEN MITOCHONDRIA UNDERGO PROFICIENT TRANSLOWICATION TO MITOCHONDRIA, THE DRP MIGHT FORM HIGHER STRUCTURES TO PROMOTE MIGHT O KONTRIAL FISSION. SO IN THE SANDY MICE WE FOUND THAT THE HIGHER OLIGMERS IN THE MITOCHONDRIA IN THE SANDY MICE IS REDUCED. D. WHEN THEY EXPRESS THIS, WE CAN INCREASE THE HIGHER ORDER STRUCTURES IN MITOCHONDRIA, BUT WE ALSO EXPRESS SANDY 1 A WE COULDN'T CHANGE THE BRP WITH THE OLIGO MYSELFATION. SO THESE RESULTS INDICATE THAT THIS BINDING CAN PROMOTE THE OLIGMERRIZATION OF MITOCHONDRIA AND ALSO WE DEMONSTRATE OUT MITOCHONDRIA BUT THIS BINDING CAN BIND TO BRP1 USING CO AMINO PRECIPITATION EXPERIMENT. SO NOW WE KNOW THAT IN ADDITION TO REGULATE DENDRITIC SPINES, THIS SPINE SYSTEM IMPORTANT FOR MITOCHONDRIA EFISSION AND OSCILLATION. WHICH POTENTIALLY CONTRIBUTE TO THE GAMMA OSCILLATION DEFECT AND SCHIZOPHRENIA IN PATIENTS. SO WHAT WE FIND IS THAT WHEN NEURONS ARE ENGAGED BY GAMMA STIMULATION AND THEY ARE GOING GAMMA OSCILLATION, THIS BINDING WILL TRANSLOCATE TO MITOCHONDRIA WHERE IT WILL BIND TO DRP1 TO PROMOTE DRP 1 OLIGMYSELFATION AND THEN THE DRP1 WILL PROMOTE MITOCHONDRIAIAL 1ENTIOUS FICIENT TO THE SYNAPSES TO PROMOTE FACILITATE THE SYNAPTIC ACTIVATION AT HIGH FREQUENCIES. OKAY, SO NOW SO FAR WHAT I TELL YOU IS ON THE SUPPORTING OF MITOCHONDRIA IN SYNAPSE DEVELOPMENT AND SYNAPTIC ACTIVITY. SO MITOCHONDRIA ALSO CAN DO ACTIVE THINGS TO SYNAPSES, SO WE FOUND OUT IT CAN ALSO CAUSE SYNAPTIC DEPRESSION AND THIS IS MEDIATED BY ANOTHER PATHWAY ON MITOCHONDRIA. WHICH IS THE MITOCHONDRIA APOPTOSIS PATHWAY. SO WE KNOW THAT APOPTOSIS IS THE PROGRAM CELLS PATHWAY AND THE KEY MOLECULE OF APOPTOSIS IS A KASP A RIPATION. THIS IS ACTIVITY DURING APOPTOSIS BY 2 INTRA CELLULAR PATHWAYS, WOIS A DEATH RECEPTOR PATHWAY AND THE OTHER IS THE MITOCHONDRIA PATHWAY. SO WHEN THE MITOCHONDRIA POGHT WAY IS STIMULATED, THE MITOCHONDRIAL PERMEABLE IS CHANGED WHICH RELEASE TO THE CYTOCHROME SEE INTO THE CYTOCHOAM. SO THEN IT WILL ACT VAILT CASPACE 9 AND 3, AND THEN IT WILL CLEAVE CELLULAR SUBSTRATE TO INDUCE CELL DEATH. MITOCHONDRIA ALSO RELEASE A FEW OTHER FACTORS WHICH BIND TO INHIBITIT ON ARES TO INDIRECTLY ACTIVATE THE CASPACE. SO THESE ARE CONONICLE CELLS AS MOLECULES BUT THIS IS ALSO FOUND IN NONAPOPTOTIC CELLS INCLUDING NEURONS AND MANY GROUPS HAVE FOUND THAT IN VARIOUS CELL TYPES, AND THE SPECIES, KASP A R PACE HAVE ATOP TO THETIC FUNCTIONS SO FOR EXAMPLE IN A-CELLS AND B-CELLS, THIS IS PROLIFERATION INTO DROSOPHILA, CASP A SES CAN REGULATE SPERM DIFFERENTIATION, NEUROSENSORY DENDRITE PRUNING. IN CASP A SE3 IS ACTIVATED FOR NEURONS AND IT CAN BE ACTIVATED IN SYNAPSES AND ACT VAIGDZ OF CASP A SE WILL CAUSE SUPPRESSES OF SYNAPTIC CURRENTS. SO PROMOTE BY THESE NONAPOPTOTIC FUNCTIONS OF CASPACE, INVOLVING SYNAPTIC PLASTICITY MANY YEARS AGO. SO FIFORTD OFF WE INHIBIT THE CASPACES IN THE HIPPOCAMPAL SLICES WHEN WE INDUCE THE SYNAPTIC PLASTICITY. SO WE USE THE KASP A R SPACE INHIBITORS, AND IT'S A 3, LEHD IS CASPACE 9, AND YVAD IS 1 INHIBITOR AND FA IS 1 PEP TIDE. SO WE INDUCE LTP AND ALSO INDUCE LTP. BUT WE INDUCE THE LTB, CASPACE 3, AND CASPACE 9 INHIBITITTOR CAUSE A BLOCK WHICH IS SHOWN BY THESE YELLOW AREAS HERE. SO THIS CASPACE 3 AND 9 ARE REQUIRED FOR THE INDUCTION OF LTP BUT NOT LTD, WHEN WE FORM THIS IN THE IMK OUT MICE, THE LTP IS NORMAL BUT LTD IS BLOCKED. THESE ARE ACTIVATED BY THE MITOCHONDRIA, SO THE PATHWAY AS APOPTOSIS DURING LTD. SO CASPACE ACTIVATION BY MITOCHONDRIA IS REGULATED BY THE BCL TO PROTEINS BASED ON APOPTOSIS LITERATURE, SO THE BCL 2 FAMILY PROTEINS ALL HAVE THE BH CONSERVED DOMAIN AND BASED ON FUNCTIONS THESE PROTEINS CAN BE DIVIDED INTO 2 GROUPS. ONE IS THE ANTIAPOPTOTIC AND THE OTHER 1 IS A PRO APOPTOTIC, SO THESE CAN PROMOTE THE CBDs AND ACTIVATE THE CASPACE, SO--SORRY, THE BCELLS OF THE PROTEIN FOR THE CHROMOSOME, AND THE INHIBITORS CASPACE ACTIVATION, THE BCL PROTEIN PROMOTES THOSE AND PROMOTES CASPACE ACTIVATION. IN THESE BAX, AND BIDRKS--BID AND BAD CAN PROMOTE THE ACTIVATION. SO WE TESTED WHETHER THESE 3 BCL PROTEINS ARE INVOLVING CASPACE PROPOTION IN LTD. WE KNOCKED DOWN THESE PROTEINS USING SIRNA AND WE FOUND IT HAS NO IMPACT ON LTD. BUT THE BAD AND THE BACKS BLOCK LTD. WE PERFORM THIS IN KNOCK OUT MICE. AND THE LTP IS NOW CHANGED BUT LTD IS BLOCKED SO THIS RESULTS INDICATING THAT CASPACE IS ACTIVATED AND THE MITOCHONDRIA IN LTD. SO, MITOCHONDRIA ACTIVATION IN CASPACE IS MAWN INDUCED CELL DETHS THEN WHY WE DO NOT SEE IT IN LTD. IT TURNS OUT THIS IS THE KINETICS AND THE LEVEL OF CASPACE ACTIVATION IN DIFFERENT LTD AND APOPTOSIS. SO DURING LTD, WE OBSERVE THE ACTIVATION, THIS IS CASPACE ACTIVITY. SO FOR EXAMPLE, CAS PACE IS QUICKLY ACTIVATED ABOUT 10 MINUTES AFTER THE LTD INDUCTION BUT THEN THE CASPACE LEVEL DOESN'T REACH VERY HIGH LEVEL AND IT QUICKLY RETURN TO PRESTIMMULATION BASE LINE AFTER STIMULATION. BY CONTRACT, DURING APOPEITOSEIS, CASPACE ACTIVATION IS DELAYED AND IT TAKES A FEW HOURS TO ACTIVATE CASPACE, BUT ONCE CASPACE IS ACTIVATED IT CAN REACH VERY HIGH LEVEL AND STAY AT HIGH LEVELS UNTIL THE CELL DIE. SO WE HAVE IN THE EXPERIMENTS WE HAVE SHOWN THAT THE LOW AND THE TREND IN ACTIVATION IS KEY TO PREVENT CELL DEATHS. AND ALSO, WE HAVE ALSO DELINEATED SIGNAL PATHWAYS THAT MEDIATED CASPACE ACTIVATION IN LTD. SO IT TURNS OUT IT'S THESE TYPE OF CASPACE ACTIVATION IS DEPENDENT IN THE NMDA RECEPTORS SO WHEN THE RECEPTOR IS ACTIVATED THE KALTSIUM IN THE CELLS WILL ACTIVATE THE CALCIUM CALCINEURIN AND PP1. IT WILL THEN ACTIVATE BAD WHICH LEAD TO THE TRANSLOCATION OF BAD FROM CYTOSOL TO MITOCHONDRIA AND ON THE MITOCHONDRIA, THAT WILL BAD WILL BIND TO BACKS. BAX IS NORMAL INHIBITED BY BCLXL, SO BYPASSING OF BAD WITH BAX WILL REMOVE INHIBITION OF BCLSL, SO NOW BAX CAN FORM ON THE MITOCHONDRIA WHICH LEADS TO THE RELEASE OF CYTOCHROME SEE CHEN ACTIVATION OF CASYSTEM PACE 9 AND 3. AND THEN CASPACE 3, HOW DOES CASPACE 3 INDUCE LTD, I--SO WE COLLAB 8 WITH SANDY MARKY IN THE INSTITUTE AND WE FIND THAT THIS IS A GAP 43 FOR THIS RATE. THIS CASPACE 3, IT IS REQUIRED FOR ENDOSIGNIFYITOSEIS OF EMPIRE RECEPTORS THEREBY REDUCING SYNAPTIC STRESS. OKAY, SO THAT'S ALL THE DAT A WILL SHOW TODAY. SO BASICALLY WHAT I FOUND THAT MITOCHONDRIA ARE VERY IMPORTANT FOR SYNAPTIC FUNCTION. THIS IS BECAUSE MITOCHONDRIA HAS SO MANY DIFFERENT ROLES IN SYNAPSES. SO FIRST OFF, JUST THE AMOUNT OF MITOCHONDRIA IN NEURONS DETERMINED IS IMPORTANT DETERMINING FACTOR FOR THE NUMBER OF SYNAPSES AND SPINES. AWLINGS SECONDLY THE SUBSEWNAL INTRIEWKS IS RELATIVE TO SYNAPTIC ACTIVITY AND IN ADDITION TO THE AMOUNT AND LOCALIZATION, MITOCHONDRIA DYNAMICS IS ALSO IMPORTANT FOR SINAMENTIC ACTIVATION, IN PARTICULAR GAMMA OSCILLATION IS REQUIRED FOR--REQUIRES MITOCHONDRIA EFFICIENT AND IT'S INTERESTING THAT THE MITOCHONDRIA EFFICIENT IN GAMMA OSCILLATION IS REGULATED BY THE SCHIZOPHRENIA RISK GTPAND NDRP1, THIS MIGHT BE A MECHANISM THAT ALSO CONTRIBUTE TO THE GAMMA OSCILLATION IMPAIRMENT IN SCHIZOPHRENIA AND LASTLY WE ALSO FOUND THAT MITOCHONDRIA IS INVOFFED IN SYNAPTIC PLASTICITY AND THIS IS MEDIATED BY THE CONONICAL APOPTOSIS PATHWAY. BUT THIS LTD THIS PATHWAY IS ONLY MODERATELY ACIVATED WHICH DOESN'T LEAD TO CELL DEATH BUT INSTEAD LEADS TO ENDOSIGNIFYITOSEIS OF RECEPTORSRECEPTORS AND SYNAPTIC DEPRESSION. OKAY, SO THESE ARE THE PEOPLE FROM MY LAB, FORMER AND CURRENT LAB MEMBERS. SO THE DOCTORS HAVE BEEN WORKING ON THE PATHWAYS, AND MORE DOCTORS HAVE WORKEDOT SPINE DEVELOPMENT PROJECTS AND COLLEAGUES HAVE WORKED ON THE FINDINGS AND THERE ARE ALSO OTHER PEOPLE IN THE LAB ALSO CONTRIBUTE TO THIS PROJECT AND I WOULD LIKE TO THANK MANY OF OUR COLLABORATORS AND THEN THE FACULTY ITSELF, NIMH HELP ME TO COMPLOAT THESE PROJECTS. THANK YOU VERY MUCH. [APPLAUSE ] >> THANK YOU. WE HAVE TIME FOR QUESTIONS IF YOU COULD USE THE MICROPHONES BECAUSE WE'RE TRANSMITTING OUTSIDE OF THE NIH. QUESTIONS? YES? >> SO I HAVE 2 QUESTIONS, 1 WAS THE PART THAT THE DYSBINDIN 1 AND MITOCHONDRIA AND INFUSION AND GAMMA OSCILLATION MAKE VERY MUCH SENSE TO ME, WHAT I DIDN'T GET IS THAT THE AGE SPECIFIC EFFECT OF THE SPINE, HOW THEY ARE LINKED WITH THE COMPONENT THAT PLAYS A ROLE FOR THE SPINE NUMBERS. SO IN NIGH CONFUSION I DON'T REMEMBER IF IT WAS THE SANDY KNOCK OUT MOUSE BUT THE NORMALITY IN TERMS OF THE SPINE WAS SPECIFIC AT LIKE 2 OR 3 WEEKS OR 3-4 WEEKS AT THE YOUNG AGE. HOW THEY LINKED WITH THESE PLAYERS, WHETHER THEY'RE RELATED TO THEIR EXPRESSIONS OR IN DIFFERENT AGES THAT IS 1 PART. THE SECOND 1 WAS IF YOU--SO MOST OF THE COVERAGE IN THE NEURONS, NOT ALL BUT MOST OF THEM DON'T HAVE SPINE AND IF YOU LOOK AT THE GABAERGIC NEURONS IN THIS SANDY MOUSE, WHETHER THE MITOCHONDRIA HAVE IS VERY ELONGATED OR EXIST THERE OR THE MECH NICHES ARE COMPLOATLY DIFFERENT? SO IF YOU COULD COMMENT ON THAT THAT WOULD BE-- >> YEAH, THAT GOOD QUESTION. FIRST OF ALL I DIDN'T WILL YOU WHY THERE'S AGE SPECIFIC EFFECT ON SPINES. SO IT TURNS OUT THIS IS A--BECAUSE OF TIME, THE INTEREST OF TIME, THIS IS FOR THE SPINES ALSO REQUIRES THE THE GLUE N2 B RECEPTOR AND IT'S HIGH AND IN THE NEURONS AND THEY START TO PICK UP DURING ADOLESCENCE AND THEN START TO DROP AGAIN IN THE ADULTHOOD AND THEN ONLY DURING THE ADOLESCENCE AND EXPRESS AT THE SUFFICIENT LEVEL, AND HELP THIS BINDING TO REGULATE DENDRITIC SPINES AND ALTHOUGH THIS TIGHT WINDOW IS NOT ENOUGH GOING TO BE TO YOU KNOW PUSH ALL THIS BINDING FUNCTION IN SPINES. AND THEN FOR THE SECOND QUESTION, THE REASON--YEAH, NO, THE GAMMA OSCILLATION HAS A LOT TO DO WITH BADGAERGIC CELLS AND THE REASON WE LOOKED AT THE GABAERGIC CELLS IN THE MUTANT MICE IS THAT THERE'S OTHER PEOPLE, HAVE SHOWN THAT THIS BIND SUGGEST NOT EXPRESSED IN GABAERGIC CELLS, ONLY IN HIPPO CAMPUS, NOT SHOWN IN LITTLER REGIONS IN THE SAME SCENARIO, BUT BECAUSE OF THAT WE START TO LOCK AT MITOCHONDRIA AND THE SPINES IN THE EXCITATORY NEURONS. AND WE HAVEN'T LOOKED AT THE MITOCHONDRIA IN THE GABAERGIC CELLS BUT THE REST EXPERIMENT, THIS WAS A LIGHT INDUCED SYSTEM AND THE PSD95, ALL THE CONTRUCT OF THE EXPRESSION IS EXPRESSED IN THE DPLIEWTA MITTERGIC CELLS WHICH IS CONSISTENT WITH THE THEDYSBINDIN FACTOR HAS TO DO WITH THE GAMMA AND THE MITOCHONDRIA DEFICIENT EFFECT. I HAVE A GENERAL-- >> I HAVE A GENERAL QUESTION ABOUT MITOCHONDRIA AND MANNESTATIONS THERE ARE A LOT OF DISORDERS THAT EFFECT MITOCHONDRIA, AND MANY MITOCHONDRIA DISORDERS ARE EFFECTED IN THE MUSCULAR, NEUROLOGICAL. THERE'S STORIES ABOUT MITOCHONDRIA DEFECTS IN PARKINSON'S DISEASE AND I SEE TOM AND SYNDROMIC DEAFNESS SYNDROME WHICH IS MITOCHONDRIA ISSUES. DO YOU THINK THIS IS A GENERAL MECHANISM THAT ACCOUNTS FOR SOME OF THE HARD TO EXPLAIN NEUROLOGICAL SYMPTOMS THAT ARE SEEN IN PATIENTS WITH MITOCHONDRIAL PROBLEMS? >> YEAH, I THINK THAT'S A VERY GOOD QUESTION. I THINK IN THOSE VERY SEVERE LIKE MITOCHONDRIA DISEASES, OR LIKE IN PARKINSON DISEASES, THE MITOCHONDRIA HAVE BEEN SO DAMAGED, OR SO POOR FUNCTIONAL. SO THEN THAT PROBABLY IS LIKE A GENERAL METABOLIC REDUCTION OR MITOCHONDRIA FUNCTION IS THE MAJOR--IS THE MAIN REASON OF THESE PROBLEMS. BUT IN THIS SCHIZOPHRENIA OR OTHERS PSYCHEIATIC DISORDERS, I THINK THE MITOCHONDRIA DEFICIENT IS NOT THAT SEVERE AS IN THE MITOCHONDRIA DISEASES. SO IN GENERAL, THEY DON'T HAVE THE IMPAIRMENT, THEY ONLY SHOW UP IN THIS VERY CHALLENGING COGNITIVE PATH. SPECIFICALLY RELY ON THESE HIGH FREQUENCY NEUROACTIVITY IN THIS EFFICIENT. >> ANY OTHER QUESTIONS? OKAY, IF NOT, THANK YOU VERY MUCH FOR A STIMULATING TALK. [APPLAUSE ]