Astrocyte SEMA3C reduction improves Rett Syndrome phenotypes.

During typical neurodevelopment, astrocytes secrete proteins that support neuronal connectivity. This process is disrupted in Rett Syndrome (RTT), a regressive neurodevelopmental disorder characterized by motor, sensory, and cognitive impairments. While astrocytes typically promote neuron outgrowth, co-culture of RTT astrocytes with wildtype neurons inhibits their outgrowth, implicating secreted astrocyte factors in RTT pathology. However, the specific factors and their contributions to RTT deficits remain poorly defined. To address this, we focused on the class 3 semaphorin SEMA3C, which shows increased astrocyte secretion in RTT and other neurodevelopmental disorders. Using astrocyte and neuron cell culture, we find that SEMA3C is inhibitory to dendrite outgrowth via PLXND1 and NRP2 receptors in cortical neurons. Genetic reduction of astrocyte SEMA3C in female RTT model mice enhances dendritic arborization and normalizes synaptic activity. Behaviorally, astrocyte SEMA3C reduction normalizes visual acuity and motor behavior, which are established clinical features in RTT. Together, these findings identify astrocyte SEMA3C as a contributor to RTT pathology and highlight the SEMA3C-NRP2- PLXND1 signaling pathway as a potential therapeutic target in disordered neurodevelopment.