Control of striatal circuit development by the chromatin regulator <i>Zswim6</i>.

Abstract

The pathophysiology of neurodevelopmental disorders involves vulnerable neural populations, including striatal circuitry, and convergent molecular nodes, including chromatin regulation and synapse function. Despite this, how epigenetic regulation regulates striatal development is understudied. Recurrent de novo mutations in <i>Zswim6</i> are associated with intellectual disability and autism. We demonstrate that ZSWIM6 localizes to the nucleus where it associates with repressive chromatin regulators. Disruption of <i>Zswim6</i> in ventral telencephalic progenitors leads to increased chromatin accessibility and transcriptional dysregulation. Ablating <i>Zswim6</i> in either striatal direct or indirect pathway spiny projection neurons resulted in similar cell-autonomous changes in excitatory but not inhibitory synaptic transmission. Specifically, <i>Zswim6</i> disruption altered the desensitization properties of AMPA receptors, leading to enhanced synaptic recruitment of SPNs, explaining SPN-subtype specific effects on activity and behavioral sub-structure. Last, adult deletion of <i>Zswim6</i> identified a continuing role in the maintenance of mature striatal synapses. Together, we describe a mechanistic role for <i>Zswim6</i> in the epigenetic control of striatal synaptic development.