Chemogenetic Activation of Prefrontal Cortex Rescues Synaptic and Behavioral Deficits in a Mouse Model of 16p11.2 Deletion Syndrome
Chemogenetic Activation of Prefrontal Cortex Rescues Synaptic and Behavioral Deficits in a Mouse Model of 16p11.2 Deletion Syndrome
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DOI：
10.1523/jneurosci.0149-18.2018
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发表时间：
2018-06-27
影响因子：
5.3
通讯作者：
Yan, Zhen
中科院分区：
文献类型：
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作者：
Wang, Wei;Rein, Benjamin;Yan, Zhen
人类16p11.2基因位点的微缺失与自闭症谱系障碍（ASD）和智力残疾有关，并可能导致其他一些神经发育缺陷。携带16p11.2缺失（16p11(+/-)）的转基因小鼠表现出与人类16p11.2缺失综合征患者相似的表型，但这些表型的分子机制和治疗策略尚不清楚。在这项研究中，我们发现雄性和雌性16p11（+/-）小鼠在内侧前额叶皮层（mPFC）中都表现出NMDA受体（NMDAR）功能缺陷，这是一个对高级“执行”功能至关重要的大脑区域。camkii驱动的Gq-DREADD （gq偶联设计物受体，由设计物药物单独激活）激活mPFC锥体神经元的活性，导致16p11（+/-）小鼠NR2B亚基磷酸化显著增加，NMDAR功能恢复，认知和社交障碍改善。这些结果表明，PFC NMDAR功能减退可能有助于16p11.2缺失综合征的病理生理，恢复PFC活性足以挽救行为缺陷。
Microdeletion of the human 16p11.2 gene locus has been linked to autism spectrum disorder (ASD) and intellectual disability and confers risk for a number of other neurodevelopmental deficits. Transgenic mice carrying 16p11.2 deletion (16p11(+/-)) display phenotypes reminiscent of those in human patients with 16p11.2 deletion syndrome, but the molecular mechanisms and treatment strategies for these phenotypes remain unknown. In this study, we have found that both male and female 16p11(+/-) mice exhibit deficient NMDA receptor (NMDAR) function in the medial prefrontal cortex (mPFC), a brain region critical for high-level "executive" functions. Elevating the activity of mPFC pyramidal neurons with a CaMKII-driven Gq-DREADD (Gq-coupled designer receptors exclusively activated by designer drugs) led to the significant increase of NR2B subunit phosphorylation and the restoration of NMDAR function, as well as the amelioration of cognitive and social impairments in 16p11(+/-) mice. These results suggest that NMDAR hypofunction in PFC may contribute to the pathophysiology of 16p11.2 deletion syndrome and that restoring PFC activity is sufficient to rescue the behavioral deficits.