A DYNAMIC SYNAPTIC SENSOR CONTROLLING HIPPOCAMPAL CA3 CIRCUIT FUNCTION - SUMMARY: MOMENT-TO-MOMENT CHANGES IN SYNAPTIC STRENGTH ARE A DYNAMIC PROPERTY OF MANY SYNAPSES INCLUDING IN REGIONS OF THE BRAIN KNOWN TO BE IMPORTANT FOR EPISODIC MEMORIES. IN THE HIPPOCAMPUS SYNAPTIC TRANSMISSION AT MOSSY FIBER (MF) SYNAPSES BETWEEN DENTATE GYRUS (DG) GRANULE CELLS AND CA3 PYRAMIDAL CELLS, DISPLAYS A LARGE DYNAMIC RANGE OF RELEASE THAT ACTS AS A HIGH PASS FILTER FOR ACTIVATING CA3 NEURONS DURING HIGH FREQUENCY BURSTS IN THE DG. IT HAS BEEN PROPOSED THAT THE MF CONNECTION IS A TEACHING SIGNAL THAT IS CRITICAL FOR THE ABILITY OF THE CA3 NETWORK TO ENCODE THE DETAILS NECESSARY TO SEPARATE SIMILAR INSTANCES AS DISTINCT EPISODIC MEMORIES. DESPITE THE POTENTIAL IMPORTANCE OF MF SYNAPTIC FACILITATION TO THE SEPARATION OF SIMILAR PATTERNS, DIRECT EMPIRICAL EVIDENCE FOR THIS HAS BEEN LACKING. THE GOAL OF THIS PROPOSAL IS TO TEST HOW THE UNIQUE DYNAMIC PROPERTIES OF MF SYNAPSES CONTRIBUTE TO THE ABILITY OF AN ANIMAL TO DISTINGUISH SIMILAR SPATIAL REPRESENTATIONS. WE WILL TAKE ADVANTAGE OF THE FINDING THAT A SPECIALIZED PRESYNAPTIC CA2+ SENSOR, WITH HIGH AFFINITY AND SLOW KINETICS, IS THE KEY TO THE LARGE ACTIVITY-DEPENDENT FACILITATION OF RELEASE OF NEUROTRANSMITTER AT MF SYNAPSES. WE PROPOSE THAT ELIMINATION OF THIS SENSOR IN MF SYNAPSES IN A NEWLY CREATED CONDITIONAL KNOCKOUT ANIMAL WILL 1. ALTER THE DYNAMICS OF THE MF SYNAPSE, 2. DISRUPT THE HIGH PASS FILTER PROPERTIES OF THE CA3 CIRCUIT AND 3. ULTIMATELY IMPACT SPECIFIC COGNITIVE PROCESSES THAT IMPAIR THE ABILITY OF MICE TO SEPARATE SIMILAR PATTERNS IN SPACE. THIS SHORT, FOCUSED PROJECT IS DESIGNED TO TEST A CIRCUMSCRIBED QUESTION THAT WILL EXPLICITLY ESTABLISH WHETHER MF SYNAPTIC DYNAMICS CAN MAP ONTO COGNITIVE PROCESSES THAT UNDERLIE PATTERN SEPARATION.