Neurexin1α differentially regulates synaptic efficacy within striatal circuits

Mutations in genes essential for synaptic function, such as the presynaptic adhesion molecule Neurexin1 alpha (Nrxn1 alpha), 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 impairment may represent a recurrent pathway to disease. Here, we test the functional relevance of Nrxn1 alpha in striatal circuits by employing optogenetic-mediated afferent recruitment of dorsal prefrontal cortical (dPFC) and parafascicular thalamic connections onto dorsomedial striatal (DMS) spiny projection neurons (SPNs). For dPFC-DMS circuits, we find decreased synaptic strength specifically onto indirect pathway SPNs in both Nrxn1 alpha(+/-) and Nrxn1 alpha(-/-) mice, driven by reductions in neurotransmitter release. In contrast, thalamic excitatory inputs to DMS exhibit relatively normal excitatory synaptic strength despite changes in synaptic N-methyl-D-aspartate receptor (NMDAR) content. These findings suggest that dysregulation of Nrxn1 alpha modulates striatal function in an input- and target-specific manner.

Automated summary

In the striatal circuitry, dysregulation of Nrxn1α specifically affects synaptic strength onto the indirect pathway SPNs, while thalamic excitatory inputs to DMS exhibit relatively normal excitatory synaptic strength despite changes in synaptic NMDAR content. This suggests that Nrxn1α modulates striatal function in an input- and target-specific manner.