Department of Neurobiology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Division of Life Science, Division of Biomedical Engineering and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Neuron. 2018 Mar 21;97(6):1253-1260.e7. doi: 10.1016/j.neuron.2018.02.001. Epub 2018 Mar 1.
Neuroligins (NLs) are critical for synapse formation and function. NL3 R451C is an autism-associated mutation. NL3 R451C knockin (KI) mice exhibit autistic behavioral abnormalities, including social novelty deficits. However, neither the brain regions involved in social novelty nor the underlying mechanisms are clearly understood. Here, we found decreased excitability of fast-spiking interneurons and dysfunction of gamma oscillation in the medial prefrontal cortex (mPFC), which contributed to the social novelty deficit in the KI mice. Neuronal firing rates and phase-coding abnormalities were also detected in the KI mice during social interactions. Interestingly, optogenetic stimulation of parvalbumin interneurons in the mPFC at 40 Hz nested at 8 Hz positively modulated the social behaviors of mice and rescued the social novelty deficit in the KI mice. Our findings suggest that gamma oscillation dysfunction in the mPFC leads to social deficits in autism, and manipulating mPFC PV interneurons may reverse the deficits in adulthood.
神经连接蛋白（NLs）对于突触的形成和功能至关重要。NL3 R451C 是一种与自闭症相关的突变。NL3 R451C 基因敲入（KI）小鼠表现出自闭症相关的行为异常，包括社交新颖性缺陷。然而，涉及社交新颖性的脑区以及潜在的机制尚不清楚。在这里，我们发现内侧前额叶皮层（mPFC）中的快速放电中间神经元兴奋性降低和γ振荡功能障碍，这导致了 KI 小鼠的社交新颖性缺陷。在社交互动过程中，我们还检测到 KI 小鼠的神经元放电率和相位编码异常。有趣的是，mPFC 中的 PV 中间神经元的光遗传学刺激以 40 Hz 的频率嵌套在 8 Hz 中，可正向调节小鼠的社交行为，并可挽救 KI 小鼠的社交新颖性缺陷。我们的研究结果表明，mPFC 中的 γ 振荡功能障碍导致自闭症中的社交缺陷，而操纵 mPFC PV 中间神经元可能会在成年期逆转这些缺陷。
