NMDA receptor hypofunction underlies deficits in parvalbumin interneurons and social behavior in neuroligin 3 R451C knockin mice
NMDA receptor hypofunction underlies deficits in parvalbumin interneurons and social behavior in neuroligin 3 R451C knockin mice
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NMDA 受体功能低下是 Neuroligin 3 R451C 敲入小鼠小白蛋白中间神经元和社会行为缺陷的基础
DOI：
10.1016/j.celrep.2022.111771
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发表时间：
2022-12-06
期刊：
影响因子：
8.8
通讯作者：
Luo, Jian-hong
中科院分区：
文献类型：
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作者：
Cao, Wei;Li, Jia-hui;Luo, Jian-hong
神经连接素（Neuroligins，NLs）是一个突触后细胞粘附分子家族，与孤独症谱系障碍有关。我们已经报道了内侧前额叶皮层（mPFC）功能障碍导致的社会def-territory在一个NL 3 R451 C敲入（KI）小鼠模型的自闭症。然而，潜在的分子机制仍不清楚。在此，我们发现KI小鼠mPFC中N-甲基-D-天冬氨酸受体（NMDAR）功能和小白蛋白阳性（PV+）中间神经元数量和表达减少。选择性敲低mPFC PV+中间神经元中的NMDAR亚基GluN 1降低其内在兴奋性。通过其部分激动剂D-环丝氨酸恢复NMDAR功能拯救KI小鼠中的PV+中间神经元功能障碍和社交缺陷。有趣的是，在青春期早期给予D-环丝氨酸可防止成年KI小鼠出现社交缺陷。总之，我们的研究结果表明，NMDAR功能低下和由此产生的PV+中间神经元功能障碍的mPFC可能构成了一个中心节点的发病机制，在KI小鼠的社会缺陷。
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.