Project Grant F30AG096950

AN IN VIVO EXPLORATION OF THE EFFECT OF CORTICOSTRIATAL GLUTAMATE IN LEWY BODY DEMENTIAS - PROJECT SUMMARY LEWY BODY DEMENTIA (LBD) IS COMPRISED OF THE CLINICAL DISORDERS PARKINSON'S DISEASE DEMENTIA (PDD) AND DEMENTIA WITH LEWY BODIES (DLB) AND IS THE SECOND MOST COMMON FORM OF DEMENTIA. LBD AFFECTS WELL OVER ONE MILLION AMERICANS, HIGHLIGHTING A GROWING CLINICAL AND ECONOMIC BURDEN. PDD PATIENTS EXHIBIT IMPAIRMENTS IN MOTOR PLANNING OF MOVEMENTS, DEMONSTRATING POOR PERFORMANCE IN VISUOSPATIAL DOMAIN EXECUTIVE FUNCTION TASKS. LBD IS PATHOLOGICALLY CHARACTERIZED BY THE ACCUMULATION OF INSOLUBLE AGGREGATES OF MISFOLDED A-SYNUCLEIN CALLED LEWY PATHOLOGY (LP). MODEL SYSTEMS OF PD DEMONSTRATE A PREPONDERANCE OF CORTICAL LP ACCUMULATES IN LAYER 5 INTRATELENCEPHALIC NEURONS IN THE CORTEX WHICH SEND GLUTAMATERGIC PROJECTIONS TO THE STRIATUM. HOWEVER, DESPITE THE EXTENSIVE BURDEN OF LP IN THE CORTEX, LITTLE IS KNOWN ABOUT ITS EFFECTS ON CORTICOSTRIATAL SYNAPTIC GLUTAMATE RELEASE. THUS THE OVERALL GOAL OF THIS PROJECT IS TO EVALUATE THE EFFECTS OF CORTICAL LEWY PATHOLOGY ON GLUTAMATERGIC SYNAPTIC TRANSMISSION AND PLANNED MOTOR BEHAVIOR IN MOUSE MODELS. WORK FROM THE LAB OF DR. LAURA VOLPICELLI-DALEY, CO-SPONSOR OF THE PI, ESTABLISHED THAT INJECTING PREFORMED FIBRILS (PFFS) OF A-SYNUCLEIN INTO THE CORTEX LEADS TO ROBUST LAYER 5 LP AND REDUCED PRESYNAPTIC FUNCTION IN SLICE ELECTROPHYSIOLOGICAL RECORDINGS OF STRIATUM EX VIVO. IN THE LAB OF DR. ANDREW HARDAWAY, CO-SPONSOR OF THE PI, THE PI HAS DEVELOPED A PROTOCOL FOR THE EXPLORATION OF SYNAPTIC GLUTAMATE RELEASE IN THE STRIATUM OF CORTICAL-PFF INJECTED MICE IN VIVO UTILIZING THE NOVEL BIOSENSOR, IGLUSNFR3. IGLUSNFR3 BINDS GLUTAMATE WITH HIGH AFFINITY TO OBSERVE SYNAPTIC GLUTAMATE IN FREELY MOVING MICE WITH HIGH TEMPORAL RESOLUTION. THIS TECHNIQUE WILL BE COUPLED WITH BEHAVIORAL ASSESSMENTS AND OPTOGENETIC STIMULATION TO PROBE THE FUNCTIONAL CONSEQUENCES OF CORTICOSTRIATAL LP LONGITUDINALLY. THUS, THE CENTRAL HYPOTHESIS IS THAT LEWY PATHOLOGY IN CORTICOSTRIATAL NEURONS WILL LEAD TO REDUCED STRIATAL GLUTAMATE DURING M2 OPTOGENETIC STIMULATION AND WILL CORRESPOND TO IMPAIRMENTS IN BEHAVIOR IN PFF- INJECTED MICE. THROUGH THIS PROPOSED WORK, THE PI WILL CONTINUE TO LEARN VALUABLE TECHNIQUES, SUCH AS FIBER PHOTOMETRY, OPTOGENETICS, HIGH RESOLUTION MICROSCOPY, AND CODING SKILLS FOR COMPLEX DATA ANALYSES. THE PROPOSED TRAINING PLAN IS SPONSORED BY THE PROJECT MENTORS, DR. LAURA VOLPICELLI-DALEY AND DR. ANDREW HARDAWAY. THE OVERALL GOAL OF THE TRAINING PLAN IS TO PROVIDE THE PI WITH A SOLID FOUNDATION FOR A SUCCESSFUL CAREER AS A PHYSICIAN SCIENTIST. A PROJECT BASED IN TRANSLATIONAL APPROACHES, WHILE FOCUSED ON A DISEASE-ORIENTED PATHOGENESIS, IS THE IDEAL TRAINING ENVIRONMENT FOR ANY ASPIRING PHYSICIAN SCIENTIST.