Study on mechanisms underlying impaired sociability of a mouse model of autism spectrum disorders with Shank2 deletion

Abstract

Autism spectrum disorder is a neurodevelopmental disorder that shows impaired social communication and interaction and limited and repetitive behavioral patterns. Although dysfunction of NMDA receptors and inhibitory GABA neurons was found in studies using various autism spectrum disorder animal models, it is unclear how these dysfunctions affect social cognition and behavior. In this study, we report that NMDA receptors in parvalbumin (Pv) neurons of the medial prefrontal cortex (mPFC) promote burst firing in cooperation with gap junctions, and this burst firing played an important role in the representation of social interaction targets in the mPFC. Decreased function of NMDA receptors seen in Shank2-/- mice, one of the autism spectrum disorder animal models, cause insufficient cooperation between NMDA receptors and gap junctions, and this suppresses the burst firing of mPFC Pv neurons in Shank2-/-. When burst firings were increased by optogenetic stimulation of the Pv neuron, the specificity of the representation of the social interaction target was improved in the mPFC of the Shank2-/- mice, resulting in rescue sociability. In the mice with Pv neuron-specific Shank2 deletion, there was no social impairment, but some of the other autism-like phenotypes seen in Shank2-/- mice and decreased sensitivity to pentylenetetrazole (PTZ)-induced seizure were observed. These results suggest that NMDA receptors in Pv neurons promote burst firing through cooperation with gap junctions, which is important for sociability.