SYNAPTIC AND GENETIC MECHANISMS UNDERLYING HOMEOSTATIC PLASTICITY IN PV INTERNEURONS - PROJECT SUMMARY/ABSTRACT PARVALBUMIN-EXPRESSING INHIBITORY INTERNEURONS (PVS) ARE LINCHPINS OF SYNCHRONIZED NEURAL COMPUTATION. THEY ARE SPECIALIZED TO PROVIDE RAPID PERISOMATIC INHIBITION ONTO EXCITATORY NEURONS (ENS) AND ARE THE PRIMARY SOURCE OF INHIBITORY CONTROL IN HIPPOCAMPAL CA1 - A REGION CRITICAL TO LEARNING AND MEMORY. PV DYSFUNCTION, CIRCUIT HYPERACTIVITY, AND COGNITIVE IMPAIRMENT ARE HALLMARK FEATURES OF SCHIZOPHRENIA AND ARE ALSO OBSERVED IN ANIMAL MODELS WITH TARGETED DELETION OF GLUTAMATE RECEPTORS IN PVS, IMPLICATING DISRUPTED GLUTAMATERGIC INPUT ONTO PVS AS A POTENTIAL CONTRIBUTOR TO THE DISORDER. WHILE THE UNDERLYING MECHANISMS REMAIN UNCLEAR, THE ONSET OF SCHIZOPHRENIA IN LATE ADOLESCENCE SUGGESTS CIRCUIT INSTABILITY MAY RESULT FROM A GRADUAL DETERIORATION OF PV SYNAPSE STABILITY. DECADES OF RESEARCH SUPPORT A CONTINUUM OF MECHANISMS AT DIFFERENT SPATIAL SCALES, FROM INDIVIDUAL SYNAPSES TO THE NETWORK-LEVEL, THROUGH WHICH ACTIVITY HOMEOSTASIS IS ACHIEVED IN ENS. WHILE NUMEROUS STUDIES HAVE SHOWN THAT PVS ARE PLASTIC IN LEARNING-RELATED CONTEXTS, HOW THEIR SYNAPTIC INPUTS REMODEL FOLLOWING CHRONIC ALTERATIONS IN NETWORK ACTIVITY IS NOT WELL UNDERSTOOD. SIMILARLY, HOMEOSTATIC PLASTICITY, OF INDIVIDUAL SYNAPSES ON INS HAS NOT BEEN EXPLORED IN VIVO AND THE MECHANISMS THAT ALLOW PVS TO PRESERVE STABILITY UNDER CIRCUIT CHALLENGE REMAIN POORLY UNDERSTOOD. THIS PROPOSAL WILL UTILIZE A COMBINATION OF HIGH-RESOLUTION CONFOCAL IMAGING, CIRCUIT MAPPING TECHNIQUES AND ELECTROPHYSIOLOGY TO TEST THE HYPOTHESIS THAT PV HOMEOSTATIC REMODELING HELPS MAINTAIN STABLE CIRCUIT BEHAVIOR IN THE FACE OF NETWORK CHALLENGE. IN AIM 1, I WILL EXAMINE HOW GLUTAMATERGIC SYNAPSES ONTO PVS STRUCTURALLY AND FUNCTIONALLY RESPOND TO CHRONIC CHANGES IN CIRCUIT ACTIVITY. AIM 2 THEN INVESTIGATES THE PV-ENRICHED NMDA RECEPTOR SUBUNIT GLUN2D, A SCHIZOPHRENIA RISK GENE, AS A POTENTIAL MECHANISM ENABLING PVS TO SENSE CHANGES IN LOCAL ACTIVITY AND INITIATE COMPENSATORY RESPONSES. TOGETHER SUCCESSFUL COMPLETION OF THE PROPOSED EXPERIMENTS MAY HELP IDENTIFY ENTRY POINTS FOR ADDRESSING AN UNMET NEED IN RESTORING EXCITATION ONTO PVS IN CONDITIONS CHARACTERIZED BY PV HYPOFUNCTION SUCH AS SCHIZOPHRENIA, EPILEPSY, AND AUTISM. THROUGH THIS PROPOSAL, I WILL BE THOROUGHLY TRAINED IN MOLECULAR BIOLOGY, CIRCUIT-MAPPING, ELECTROPHYSIOLOGY AND GENETIC PERTURBATION STRATEGIES. IN ADDITION, MENTORSHIP FROM DR. BYGRAVE AND CO-SPONSOR DR. DULLA WILL PROVIDE AN ENVIRONMENT WITH EXCEPTIONAL GUIDANCE AND RIGOROUS TRAINING, ACCESS TO ALL NECESSARY EQUIPMENT, AND OPPORTUNITIES FOR NETWORKING, MENTORSHIP, AND CAREER DEVELOPMENT ACTIVITIES. COLLECTIVELY, THIS PROPOSAL WILL PROVIDE ME WITH THE SCIENTIFIC TRAINING AND GROWTH NECESSARY FOR ESTABLISHING THE FOUNDATIONS FOR A FUTURE SUCCESSFUL CAREER AS AN INDEPENDENT ACADEMIC SCIENTIST.