NMDA receptor hypofunction underlies deficits in parvalbumin interneurons and social behavior in neuroligin 3 R451C knockin mice

Neuroligins (NLs), a family of postsynaptic cell-adhesion molecules, have been associated with autism spec-trum disorder. We have reported that dysfunction of the medial prefrontal cortex (mPFC) leads to social def-icits in an NL3 R451C knockin (KI) mouse model of autism. However, the underlying molecular mechanism remains unclear. Here, we find that N-methyl-D-aspartate receptor (NMDAR) function and parvalbumin-pos-itive (PV+) interneuron number and expression are reduced in the mPFC of the KI mice. Selective knockdown of NMDAR subunit GluN1 in the mPFC PV+ interneuron decreases its intrinsic excitability. Restoring NMDAR function by its partial agonist D-cycloserine rescues the PV+ interneuron dysfunction and social deficits in the KI mice. Interestingly, early D-cycloserine administration at adolescence prevents adult KI mice from social deficits. Together, our results suggest that NMDAR hypofunction and the resultant PV+ interneuron dysfunc-tion in the mPFC may constitute a central node in the pathogenesis of social deficits in the KI mice.

Automated summary

This study shows that neuroligins are involved in autism spectrum disorder, and that dysfunction of NMDA receptors and PV+ interneurons in the medial prefrontal cortex contribute to social deficits in a mouse model of autism. The researchers found that restoring NMDA receptor function with a partial agonist improved the interneuron dysfunction and prevented social deficits. These findings suggest that targeting NMDA receptors and PV+ interneurons may be a potential therapeutic strategy for autism.