Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Neuroscience Institute, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Psychology, Virginia Tech, Blacksburg, VA 24061, USA.
Cell Rep. 2022 Jun 7;39(10):110906. doi: 10.1016/j.celrep.2022.110906.
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.
社交功能障碍是自闭症谱系障碍（ASD）的核心症状之一，可能源于多个大脑区域之间的神经网络连接中断。然而，导致社交功能障碍的致病神经网络机制在很大程度上尚不清楚。在这里，我们证明了兴奋性神经元中 ASD 风险 Shank3 基因突变（ctMUT）会改变从前额叶皮层到基底外侧杏仁核的单向投射中的回路的棘突形态和兴奋性-抑制性平衡。Shank3 ctMUT 小鼠表现出社交能力下降，以及神经活动及其幅度变异性增加，这与人类 ASD 患者的神经影像学结果一致。此外，回路过度活跃破坏了社交调节神经元对社交互动事件的时间相关性。最后，光遗传学回路激活在野生型小鼠中部分再现了 Shank3 ctMUT 小鼠社交能力下降，而 Shank3 ctMUT 小鼠中的回路抑制部分挽救了社交行为。总之，这些结果突出了 Shank3 突变导致社交功能障碍的回路水平致病机制。
