MOLECULAR AND ACTIVITY CORRELATES OF SOCIAL DOMINANCE IN PREFRONTAL INTERNEURONS

Retinoic acid–induced 1 (RAI1) is a transcriptional regulator that controls the expression of genes involved in circuit assembly, neurotransmission, synaptic plasticity, and circadian rhythm. Loss of Rai1 function is strongly implicated in autism spectrum disorder (ASD), specifically in the syndromic form Smith–Magenis syndrome (SMS). As a monogenic disorder, SMS provides a tractable model to study mechanisms underlying social impairment. We used Visium HD spatial transcriptomics to determine how loss of Rai1 alters gene expression programs within the medial prefrontal cortex (mPFC), a region critical for social behavior. We observed widespread, spatially organized transcriptional dysregulation in SMS mPFC relative to control tissue, including reduced expression of activity-dependent genes. Cell-type–resolved analyses revealed subtype-specific molecular signatures within inhibitory interneurons (INs), with more extensive transcriptional changes observed in somatostatin (SST) INs. To relate these molecular alterations to circuit function and behavior, we assessed social dominance using the tube test in mice with IN subtype–specific deletion of Rai1. Vasoactive intestinal peptide (VIP) conditional knockout (cKO) mice were more dominant, whereas parvalbumin (PV) and SST cKO mice were more frequently subordinate. These behavioral differences were accompanied by increased Fos expression in interneurons lacking Rai1 following social competition in VIP and PV cKO mice, but not in SST cKO mice. Chemogenetic inhibition of prefrontal VIP or PV interneurons normalized tube test winning rates, indicating that excessive inhibitory circuit activity contributes to dominance alterations. Together, these findings indicate that coordinated activity-dependent and transcriptional alterations within prefrontal inhibitory circuits underlie changes in social dominance behavior.