Mutations in Shank3 are strongly associated with autism spectrum disorders and neural circuit changes in several brain areas, but the cellular mechanisms that underlie these defects are not understood. Homeostatic forms of plasticity allow central circuits to maintain stable function during experience-dependent development, leading us to ask whether loss of Shank3 might impair homeostatic plasticity and circuit-level compensation to perturbations. We found that Shank3 loss in vitro abolished synaptic scaling and intrinsic homeostatic plasticity, deficits that could be rescued by treatment with lithium. Further, Shank3 knockout severely compromised the in vivo ability of visual cortical circuits to recover from perturbations to sensory drive. Finally, lithium treatment ameliorated a repetitive self-grooming phenotype in Shank3 knockout mice. These findings demonstrate that Shank3 loss severely impairs the ability of central circuits to harness homeostatic mechanisms to compensate for perturbations in drive, which, in turn, may render them more vulnerable to such perturbations.

Shank3 的突变与自闭症谱系障碍和几个大脑区域的神经回路变化密切相关，但尚不清楚这些缺陷背后的细胞机制。可塑性的稳态形式允许中央电路在依赖经验的发育过程中保持稳定的功能，这导致我们询问 Shank3 的丢失是否会损害稳态可塑性和电路级对扰动的补偿。我们发现，Shank3体外缺失消除了突触缩放和内在稳态可塑性，这些缺陷可以通过锂治疗来挽救。此外，Shank3 敲除严重损害了体内视觉皮层回路从扰动恢复到感觉驱动的能力。最后，锂处理改善了 Shank3 基因敲除小鼠的重复自我修饰表型。这些发现表明，Shank3 损失严重损害了中央电路利用稳态机制来补偿驱动扰动的能力，这反过来又可能使它们更容易受到这种扰动的影响。