Interneuron Synapses: In Vivo Chemicogenetic Proteomics to Discover Developmental Brain Disorder Etiologies

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ABSTRACT: Developmental brain disorders (DBDs), such as autism, epilepsy, and schizophrenia, are neurological disorders associated with complex genetic etiologies. Emerging evidence strongly suggests that DBDs arise from disturbances between neural circuit excitation and inhibition (E/I imbalance), driven by neuronal synapse abnormalities, as well as inhibitory interneuron dysfunction. Interestingly, analyses of atypical synapse structure and aberrant interneuron function have largely been pursued independently, primarily because the tools to isolate and analyze interneuron synapses were non-existent. The unknown molecular composition and modulation of interneuron synapses is a fundamental gap in neuroscience knowledge, which limits the ability to analyze their functional contribution to DBDs. To address this critical barrier, I propose to utilize in vivo chemicogenetic proteomics (iBioID) approach to chart, for the first time, the synaptic proteomes of the two most prevalent genetically-defined interneuron subtypes, parvalbumin (PV) and somatostatin (SST) neurons. My central hypothesis is that the molecular composition of synapses in these cells is unique, reflecting their morphological and physiological differences from other synapses, such as the glutamatergic dendritic spine. I predict that interneuron synapses serve as important nodes of DBD genetic burden, which will be revealed by the discovery of their protein composition and molecular functions. The long-term goal of this project is to elucidate the mechanisms of interneuron synaptic signaling in order to identify potential novel neuropsychiatric treatment mechanisms. The primary objective of this project is to dissect the functional role of disease-relevant synaptic molecules in PV and SST neural populations. Evaluating how these candidate proteins interact in each synaptic environment will help determine how various DBDs converge on similar phenotypic outputs and improve the efficacy of clinical therapies. ! !