Neurexin1α Differentially Regulates Synaptic Efficacy within Striatal Circuits

Abstract

Mutations in genes essential for shared aspects of synaptic function throughout the CNS, such as the presynaptic adhesion molecule Neurexin1α (Nrxn1α), are strongly implicated in neuropsychiatric pathophysiology. As the input nucleus of the basal ganglia, the striatum integrates diverse excitatory projections governing cognitive and motor control, and its functional impairment underlies neuropsychiatric disorders. While prior work has emphasized Neurexins’ contributions to synaptic transmission in hippocampus and brainstem, their function in striatal circuits remains unstudied. As Nrxn1α is highly expressed at striatal inputs, we employed optogenetic-mediated afferent recruitment of dorsal prefrontal cortex-dorsomedial striatal (DMS) connections, uncovering a decrease in net synaptic strength specifically onto indirect pathway spiny neurons in both Nrxn1α+/- and Nrxn1α-/- mice, driven by reductions in transmitter release probability. In contrast, thalamic excitatory inputs to DMS demonstrated relatively normal excitatory synaptic strength. These findings suggest that dysregulation of Nrxn1α modulates striatal function in an input and target-specific manner.