Cell-type and sex-specific organization and neurexin-3 utilization at parvalbumin inhibitory synapses in ventral subiculum

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Project Summary The ventral subiculum (vSUB) is the major output structure of the ventral hippocampus and plays an integral role in the regulation of stress, fear and reward processing. Hyperactivity of vSUB is a pathophysiology common to schizophrenia and addiction disorders and is proposed to arise from reduced local inhibition onto vSUB principle neurons, identified as burst and regular spiking neurons, which engage in parallel information processing circuits. There is evidence from human patients and mouse models that inhibitory parvalbumin basket cells (PVs) in vSUB are specifically disrupted in schizophrenia. PVs are a prominent class of interneurons that provide potent inhibition of principle neurons. Despite the obvious importance of vSUB PVs to normal function and their relevance to disease, very little is known about the fundamental connectivity, properties of synaptic transmission, or molecules that govern synapses made by PV interneurons onto regular and burst spiking principle neurons of vSUB. Additionally, although sex differences in schizophrenia, addiction, and stress have been described for decades, little is known about underlying sex differences within brain regions associated with these diseases, such as vSUB. Neurexin-3 (Nrxn3), an evolutionarily conserved and essential presynaptic adhesion molecule, may exert dominant and potentially distinct control of PV synaptic properties in vSUB. Neurexins are critical for synapse specification and synaptic transmission, and Nrxn3 exhibits diverse brain region, cell type, and synapse specific functions. Notably, mutations in Nrxn3 have been repeatedly linked to schizophrenia and addiction and Nrxn3 is robustly and uniquely expressed in hippocampal PVs, indicating it plays a critical role at vSUB PV synapses and may contribute to the etiologies that underlie these disorders. The specific function(s) of Nrxn3 at PV synapses, however, has surprisingly never been described. Supported by strong preliminary data, here, I will provide a comprehensive interrogation of the cell-type- and sex-specific wiring, synaptic transmission and usage of Nrxn3 by PVs among regular and burst spiking cells in vSUB. I will employ a multi-disciplinary approach consisting of mouse genetics, viral injections, optogenetics, and molecular replacement together with electrophysiology in acute vSUB slices to assess 1) the specific function(s) of Nrxn3 at PV-regular spiking and PV-burst spiking cell synapses of male and female mice and 2) the specific Nrxn3 isoforms and domains required to regulate these functions. This project will expand our understanding of the functional organization and molecular constituents that shape inhibition within a brain region associated with schizophrenia, addiction, and stress disorders.