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^ΔC/+ 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^ΔC/+ mice are mitigated in Shank3^ΔC/+;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^ΔC/+ mice are rescued in Shank3^ΔC/+;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 Phelan-McDermid 综合征 （PMS），这些个体会表现出对压力的敏感性，从而导致行为恶化。在这里，我们使用对 PMS 具有面部效度的小鼠模型来检查压力与基因型的相互作用。在 Shank3^ΔC/+ 小鼠中，游泳应激会在锥体神经元中产生改变的转录组反应，从而影响参与突触功能、信号传导和蛋白质周转的基因和通路。Homer1a 是 Shank3-mGluR-N-甲基-D-天冬氨酸 （NMDA） 受体复合物的一部分，是超诱导的，并且与应激反应有关，因为 Shank3^ΔC/+ 小鼠中应激诱导的社交缺陷在 Shank3^ΔC/+ 中得到缓解;Homer1a^-/-小鼠。几条证据表明，Shank3 表达受 Homer1a 与 Homer 交联形式的竞争调节，并且与该模型一致，在 Shank3^ΔC/+ 小鼠中降低的 Shank3 表达和功能在 Shank3^ΔC/+ 中被挽救;Homer1a^-/-小鼠。研究强调了压力与遗传学之间的相互作用，并将注意力集中在可能导致发病机制的活动依赖性变化上。