Upregulated SEMA3C in astrocytes contributes to Rett Syndrome phenotypes

Abstract

Astrocytes support neuronal function during development through secreted proteins, yet how astrocyte-secreted cues are altered in disease states and contribute to neurodevelopmental disorders remains poorly defined. Rett syndrome (RTT) is a regressive neurodevelopmental disorder characterized by motor, sensory, and cognitive impairments. Here, we identify the class 3 semaphorin SEMA3C as an astrocyte-secreted protein that contributes to RTT pathology. We show that Sema3c expression is elevated in astrocytes in vivo in RTT model mice and find that SEMA3C is sufficient to inhibit cortical neuron dendrite outgrowth. Normalization of astrocyte SEMA3C levels in female RTT model mice rescues dendritic arborization deficits, restores synaptic activity, and improves visual acuity and motor behavior. Mechanistically, both SEMA3C and RTT astrocyte conditioned media inhibit dendrite outgrowth through PLXND1-dependent signaling. Together, these findings identify astrocyte-secreted SEMA3C as a contributor to RTT pathology and highlight SEMA3C and PLXND1 signaling as potential therapeutic targets in neurodevelopmental disorders.