4.8 Article

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

期刊

CELL REPORTS
卷 41, 期 10, 页码 -

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CELL PRESS
DOI: 10.1016/j.celrep.2022.111771

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资金

  1. National Natural Science Foundation of China [81801355, U22A20306, 3192010300, 31871418, 31970902]
  2. Young Elite Scientists Sponsorship Program by CAST [YESS20180169]
  3. China Postdoctoral Science Foundation [BX20180272, 2019M652066]
  4. Zhejiang Provincial Natural Science Foundation of China [D19H090004, LR19H090001]
  5. Key Area Research and Development Program of Guangdong Province [2019B030335001]

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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.
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.

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