Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA.
Solomon Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA; Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.
Cell Rep. 2021 Nov 16;37(7):110014. doi: 10.1016/j.celrep.2021.110014.
Mutations of SHANK3 cause Phelan-McDermid syndrome (PMS), and these individuals can exhibit sensitivity to stress, resulting in behavioral deterioration. Here, we examine the interaction of stress with genotype using a mouse model with face validity to PMS. In Shank3 mice, swim stress produces an altered transcriptomic response in pyramidal neurons that impacts genes and pathways involved in synaptic function, signaling, and protein turnover. Homer1a, which is part of the Shank3-mGluR-N-methyl-D-aspartate (NMDA) receptor complex, is super-induced and is implicated in the stress response because stress-induced social deficits in Shank3 mice are mitigated in Shank3;Homer1a mice. Several lines of evidence demonstrate that Shank3 expression is regulated by Homer1a in competition with crosslinking forms of Homer, and consistent with this model, Shank3 expression and function that are reduced in Shank3 mice are rescued in Shank3;Homer1a mice. Studies highlight the interaction between stress and genetics and focus attention on activity-dependent changes that may contribute to pathogenesis.
SHANK3 突变会导致菲兰-麦克德米德综合征（Phelan-McDermid syndrome，PMS），这些患者可能对压力敏感，导致行为恶化。在这里，我们使用具有 PMS 表面效度的小鼠模型研究了应激与基因型的相互作用。在 Shank3 小鼠中，游泳应激会导致锥体神经元中转录组反应发生改变，影响参与突触功能、信号转导和蛋白质周转的基因和途径。 Homer1a 是 Shank3-mGluR-N-甲基-D-天冬氨酸（NMDA）受体复合物的一部分，超表达，并与应激反应有关，因为 Shank3 小鼠的应激诱导的社交缺陷在 Shank3;Homer1a 小鼠中减轻。有几条证据表明，Shank3 的表达受 Homer1a 的调控，与 Homer 的交联形式竞争，与该模型一致，Shank3 表达和功能在 Shank3 小鼠中降低，在 Shank3;Homer1a 小鼠中恢复。研究强调了应激和遗传之间的相互作用，并关注可能导致发病机制的活性依赖性变化。
