Molecular Control Of Synaptic Efficacy Within Striatal Circuits

As the input nucleus of the basal ganglia, the striatum integrates diverse excitatory projections governing cognitive and motor control. Over the last decade, substantial progress has been made in the identification of striatal cell-types, distinguishing their molecular profiles and local connectivity patterns. Nevertheless, our understanding of the functional organization of striatal circuits remains limited. The studies presented in this thesis focus on delineating the synaptic properties of excitatory inputs originating from dorsal prefrontal cortex and parafascicular thalamus innervating neuronal populations within dorsal medial striatum. In these studies, we use quantitative optogenetic measures to investigate striatal projections in an input-specific manner onto distinct striatal neuronal populations. In the first study, we find a divergence between cell-type specific anatomical connectivity and measures of excitatory strength. Furthermore, we find that synaptic strength is modified according to both presynaptic region and postsynaptic cell type. As a substantial degree of synaptic function is determined by the molecular composition of individual neurons and their synapses, the second study examines the role of a cell-adhesion molecule, Neurexin1ɑ, at these synapses. We found Neurexin1ɑ, a gene with broad neuropsychiatric disease association, regulates synaptic efficacy at these synapses in an input- and postsynaptic cell type manner. Together, these studies demonstrate a significant amount of diversity observed in physiological connectivity can be attributed to presynaptic-postsynaptic interactions and their underlying molecular composition. Ultimately, forming a comprehensive map of striatal circuits will be essential in understanding how the convergence of inputs from various sources convey information for distinct behavioral functions.