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

Many autistic children are oversensitive to light touch, like clothing or gentle contact. This study used mice to understand why this happens. Researchers found that immune cells in the spinal cord remove too many connections that normally calm down nerve cells. This makes the mice overly sensitive to touch. When they blocked these immune cells, both touch sensitivity and repetitive behaviors improved. This research suggests new ways to help autistic children who struggle with touch sensitivity.

This study investigated the neural mechanisms underlying tactile hypersensitivity in autism using a maternal immune activation (MIA) mouse model. Researchers found that mechanical hypersensitivity in MIA mice resulted from overactivated PKCγ interneurons in the spinal cord. This overactivation occurred because spinal microglia excessively engulfed inhibitory synapses that normally regulate these interneurons. The study demonstrated that reducing microglia activation not only improved mechanical hypersensitivity but also reduced stereotyped behaviors.

These findings suggest that targeting spinal microglia could be a therapeutic approach for addressing tactile sensitivities commonly experienced by autistic individuals, particularly sensitivity to gentle touch or clothing friction.

Findings suggest that targeting neuroinflammation, specifically microglia activation, could help manage tactile hypersensitivity in autism. This research provides a biological basis for sensory processing difficulties and may inform development of new therapeutic approaches focusing on immune system modulation rather than behavioral interventions alone.

Study conducted only in mouse model; sample size not reported; mechanisms may not fully translate to humans; long-term effects of microglia inhibition unknown; unclear if findings apply across autism spectrum.

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.