Project Grant F31AG097085

MECHANISMS OF SYNAPSE MAINTENANCE IN THE AGING NERVOUS SYSTEM - PROJECT SUMMARY COGNITIVE DECLINE IS A MAJOR HALLMARK OF AGING. SYNAPSE LOSS AND STRUCTURAL ALTERATIONS ARE BELIEVED TO BE MAJOR CONTRIBUTING FACTORS TO NORMAL AGE-RELATED COGNITIVE DECLINE AND ARE EXACERBATED IN CASES OF NEURODEGENERATIVE DISEASES SUCH AS ALZHEIMER'S DISEASE. THE GOAL OF THIS PROJECT IS TO IDENTIFY CONSERVED MECHANISMS RESPONSIBLE FOR SYNAPSE MAINTENANCE IN AGING ANIMALS. THE SHORT LIFESPAN, INVARIANT NEURONAL CIRCUITRY, AND GENETIC TOOLS AVAILABLE IN THE INVERTEBRATE CAENORHABDITIS ELEGANS OFFER STRONG ADVANTAGES FOR STUDIES OF SYNAPSE MAINTENANCE. WHILE PRIOR STUDIES HAVE LARGELY FOCUSED ON GROSS NEURON MORPHOLOGICAL CHANGES DURING AGING, MY WORK IS FOCUSED ON UNDERSTANDING AGE-RELATED SYNAPSE CHANGES. THE FRANCIS LAB PREVIOUSLY DEMONSTRATED THAT C. ELEGANS GABAERGIC DD MOTOR NEURONS HAVE DENDRITIC SPINES WHICH SHARE MANY CHARACTERISTICS WITH MAMMALIAN DENDRITIC SPINES. MY WORK FOCUSES ON UNDERSTANDING HOW AGE IMPACTS THE NUMBER, STRUCTURE, AND FUNCTION OF DENDRITIC SPINES. MY PRELIMINARY STUDIES SUGGEST THAT DENDRITIC SPINE NUMBER IS REDUCED IN AGING ANIMALS. MY PROPOSED WORK WILL DEFINE HOW AGING IMPACTS SYNAPSE STRUCTURE AND FUNCTION (AIM 1). IN AIM 2, I WILL INVESTIGATE HOW THE CONSERVED PRESYNAPTIC ADHESION MOLECULE NRX-1/NEUREXIN-1 IMPACTS SYNAPSE MAINTENANCE WITH AGE. IN AIM 3, I WILL IDENTIFY POTENTIAL POSTSYNAPTIC TARGETS CRUCIAL FOR SYNAPSE MAINTENANCE USING PROXIMITY LABELING AND SUBSEQUENT PROTEOMIC ANALYSES. MY PROPOSED WORK WILL ADVANCE OUR UNDERSTANDING OF THE MECHANISMS REGULATING SYNAPSE MAINTENANCE IN AGING ANIMALS AND POTENTIALLY IDENTIFY NEW GENE TARGETS FOR THERAPEUTIC INTERVENTION. IMPORTANTLY, THE PROPOSED STUDIES WILL ALSO PROVIDE SIGNIFICANT OPPORTUNITIES FOR NEW TECHNICAL AND PROFESSIONAL TRAINING FOR THE APPLICANT.