Shank3(?C/+) mice exhibit altered transcriptomic response to swim stress

Shank3 is a postsynaptic protein that complexes with group 1 metabotropic, AMPA-, and NMDA-type glutamate receptors. Mutations of Shank3 are causal for Phelan-McDermid syndrome (PMS) and associated autism phenotypes. Individuals with PMS often exhibit sensitivity to novelty or stress that can result in behavioral deterioration. Here we use a Shank3 mouse model with face-validity to PMS [Shank(3?C/+)] and perform a transcriptomic analysis of principal neurons from neocortex of mice subjected to brief swim stress. Analysis reveals overrepresented pathways related to synapses accompanied by elevated expression of the immediate early gene Homer1a. In normal brain Homer1a is dynamically expressed in association with motivated behavior and mediates an essential step in sleep-related homeostatic down-scaling of synaptic proteins. This is consistent with observations that synaptic Shank3 expression requires Homer cross-linking, which is interrupted by Homer1a. Accentuated Homer 1a expression in Shank3(?C/+) results in marked reductions of Shank3 expression, changes in synapse composition and NMDA-dependent synaptic plasticity, and disruption of social motivation. Deletion of Homer1a partially mitigates stress-induced phenotypes in Shank3(?C/+) mice. Homer 1a is required for developmental plasticity, learning and memory, yet its enhanced expression in Shank3(?C/+) may underlie a vulnerability of PMS patients that highlights the challenge of clinical management. Overall design: Pyramidal Neuron mRNA profiles of Shank3(+/+) and Shank3(?C/+) mice on C57BL6 strain background with and without swim stress

Shank3是一种突触后蛋白，可与I组代谢型谷氨酸受体（group 1 metabotropic glutamate receptors）、AMPA型谷氨酸受体（AMPA-type glutamate receptors）以及NMDA型谷氨酸受体（NMDA-type glutamate receptors）形成复合物。Shank3的突变是Phelan-McDermid综合征（Phelan-McDermid syndrome, PMS）及相关自闭症表型的致病诱因。PMS患者常表现出对新异刺激或应激的敏感性，该敏感性可引发行为功能恶化。本研究采用了一种与PMS具有表面效度（face validity）的Shank3小鼠模型[Shank3(+/-)]，对经历短暂游泳应激的小鼠新皮层主神经元开展转录组分析。分析结果显示，与突触相关的通路显著富集，同时即刻早期基因Homer1a（immediate early gene Homer1a）的表达水平上调。在正常大脑中，Homer1a的表达随动机性行为发生动态变化，并介导睡眠相关突触蛋白稳态下调过程中的关键步骤。这与既往研究结论一致：突触Shank3的表达需要Homer蛋白的交联作用，而该过程会被Homer1a所阻断。Shank3(+/-)小鼠中Homer1a的表达增强会导致Shank3表达显著降低、突触组成改变以及NMDA依赖的突触可塑性异常，并破坏社交动机。敲除Homer1a可部分缓解Shank3(+/-)小鼠的应激诱导表型。Homer1a是发育可塑性、学习与记忆所必需的基因，但其在Shank3(+/-)小鼠中的高表达可能是PMS患者易感性的潜在机制，这也凸显了PMS临床管理的挑战。整体实验设计：在C57BL/6遗传背景下，对施加或未施加游泳应激的Shank3(+/+)与Shank3(+/-)小鼠的皮层锥体神经元进行mRNA表达谱分析。