Neural circuit pathology driven by Shank3 mutation disrupts social behaviors.
Neural circuit pathology driven by Shank3 mutation disrupts social behaviors.
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DOI：
10.1016/j.celrep.2022.110906
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发表时间：
2022-06-07
期刊：
影响因子：
8.8
通讯作者：
Kim, Il Hwan
中科院分区：
文献类型：
--
作者：
Kim, Sunwhi;Kim, Yong-Eun;Song, Inuk;Ujihara, Yusuke;Kim, Namsoo;Jiang, Yong-Hui;Yin, Henry H.;Lee, Tae-Ho;Kim, Il Hwan
社交功能障碍是自闭症谱系障碍（ASD）的核心症状，可能是由多个大脑区域之间的神经网络连接障碍引起的。然而，社会功能障碍背后的致病神经网络机制在很大程度上是未知的。在这里，我们证明了asd风险基因Shank3在从前额皮质到基底外侧杏仁核的单向投射中的电路选择突变（ctMUT）改变了脊柱形态和电路的兴奋-抑制平衡。Shank3 ctMUT小鼠表现出社交能力下降，神经活动及其幅度变异性升高，这与人类ASD患者的神经影像学结果一致。此外，神经回路的过度活跃破坏了社会调节神经元与社会互动事件的时间相关性。最后，野生型小鼠的光遗传回路激活部分概括了Shank3 ctMUT小鼠的社交能力降低，而Shank3 ctMUT小鼠的回路抑制部分挽救了社交行为。总的来说，这些结果强调了Shank3突变驱动社会功能障碍的回路水平致病机制。Kim等人报告说，PFC-BLA回路中独有的自闭症风险基因Shank3的缺失会导致社交功能障碍，并通过过度激活破坏社交行为调节回路的活动。类似的PFC-BLA超连通性在人类ASD患者中也可以观察到。
Dysfunctional sociability is a core symptom in autism spectrum disorder (ASD) that may arise from neural-network dysconnectivity between multiple brain regions. However, pathogenic neural-network mechanisms underlying social dysfunction are largely unknown. Here, we demonstrate that circuit-selective mutation (ctMUT) of ASD-risk Shank3 gene within a unidirectional projection from the prefrontal cortex to the basolateral amygdala alters spine morphology and excitatory-inhibitory balance of the circuit. Shank3 ctMUT mice show reduced sociability as well as elevated neural activity and its amplitude variability, which is consistent with the neuroimaging results from human ASD patients. Moreover, the circuit hyper-activity disrupts the temporal correlation of socially tuned neurons to the events of social interactions. Finally, optogenetic circuit activation in wild-type mice partially recapitulates the reduced sociability of Shank3 ctMUT mice, while circuit inhibition in Shank3 ctMUT mice partially rescues social behavior. Collectively, these results highlight a circuit-level pathogenic mechanism of Shank3 mutation that drives social dysfunction. Kim et al. report that deletion of Shank3, an autism risk gene exclusively within the PFC-BLA circuit, results in social dysfunction and disrupts social-behavior-tuned circuit activity by hyper-activation. Similar PFC-BLA hyper-connectivity is also observable in human ASD patients.
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影响因子：
30.8
作者：
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通讯作者：
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影响因子：
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通讯作者：
Rappold GA
影响因子：
11
作者：
Di Martino, A.;Yan, C-G;Li, Q.;Denio, E.;Castellanos, F. X.;Alaerts, K.;Anderson, J. S.;Assaf, M.;Bookheimer, S. Y.;Dapretto, M.;Deen, B.;Delmonte, S.;Dinstein, I.;Ertl-Wagner, B.;Fair, D. A.;Gallagher, L.;Kennedy, D. P.;Keown, C. L.;Keysers, C.;Lainhart, J. E.;Lord, C.;Luna, B.;Menon, V.;Minshew, N. J.;Monk, C. S.;Mueller, S.;Mueller, R. A.;Nebel, M. B.;Nigg, J. T.;O'Hearn, K.;Pelphrey, K. A.;Peltier, S. J.;Rudie, J. D.;Sunaert, S.;Thioux, M.;Tyszka, J. M.;Uddin, L. Q.;Verhoeven, J. S.;Wenderoth, N.;Wiggins, J. L.;Mostofsky, S. H.;Milham, M. P.
通讯作者：
Milham, M. P.