Microglia-Mediated Dysfunction of PKCγ Interneurons Underlies the Mechanical Hypersensitivity in Autism

Children with autism spectrum disorder (ASD) often exhibit heightened sensitivity to innocuous mechanical stimuli, such as gentle touch or friction from clothing. However, the neural mechanisms underlying these ASD-associated tactile deficits remain unclear. In the present study, we found that the maternal immune activation (MIA) mouse model of ASD displayed marked mechanical hypersensitivity. Following innocuous mechanical stimulation to the hind paw, protein kinase C gamma (PKCγ) excitatory interneurons were activated in the spinal dorsal horn. Importantly, the activation of PKCγ interneurons contributed to mechanical hypersensitivity in MIA mice. As the density of VGAT⁺ (vesicular GABA transporter) inhibitory synapses was significantly reduced in the perisomatic region of PKCγ interneurons, we found obvious activation of spinal microglia and increased microglia-mediated engulfment of inhibitory synapses in the spinal cord of MIA mice. Notably, inhibiting spinal microglia activation not only alleviated mechanical hypersensitivity but also significantly attenuated stereotyped behavior in MIA mice. Together, these results suggest that excessive microglia-mediated phagocytosis of inhibitory synapses increases PKCγ interneuron activation, thereby contributing to mechanical hypersensitivity in MIA mice. Thus, targeting spinal microglia may be a promising therapeutic strategy for alleviating tactile hypersensitivity associated with ASD.