The Shank3 gene encodes the major postsynaptic scaffolding protein SHANK3. Its mutation causes a syndromic form of autism spectrum disorder (ASD): Phelan-McDermid Syndrome (PMDS). It is characterized by global developmental delay, intellectual disorders (ID), ASD behavior, affective symptoms, as well as extra-cerebral symptoms. Although Shank3 deficiency causes a variety of molecular alterations, they do not suffice to explain all clinical aspects of this heterogenic syndrome. Since global gene expression alterations in Shank3 deficiency remain inadequately studied, we explored the transcriptome in vitro in primary hippocampal cells from Shank3∆11(−/−) mice, under control and lithium (Li) treatment conditions, and confirmed the findings in vivo. The Shank3∆11(−/−) genotype affected the overall transcriptome. Remarkably, extracellular matrix (ECM) and cell cycle transcriptional programs were disrupted. Accordingly, in the hippocampi of adolescent Shank3∆11(−/−) mice we found proteins of the collagen family and core cell cycle proteins downregulated. In vitro Li treatment of Shank3∆11(−/−) cells had a rescue-like effect on the ECM and cell cycle gene sets. Reversed ECM gene sets were part of a network, regulated by common transcription factors (TF) such as cAMP responsive element binding protein 1 (CREB1) and β-Catenin (CTNNB1), which are known downstream effectors of synaptic activity and targets of Li. These TFs were less abundant and/or hypo-phosphorylated in hippocampi of Shank3∆11(−/−) mice and could be rescued with Li in vitro and in vivo. Our investigations suggest the ECM compartment and cell cycle genes as new players in the pathophysiology of Shank3 deficiency, and imply involvement of transcriptional regulators, which can be modulated by Li. This work supports Li as potential drug in the management of PMDS symptoms, where a Phase III study is ongoing.

Shank3 基因编码主要的突触后支架蛋白 SHANK3。它的突变会导致自闭症谱系障碍 (ASD) 的综合症形式：费兰-麦克德米德综合症 (PMDS)。其特点是整体发育迟缓、智力障碍 (ID)、自闭症谱系障碍 (ASD) 行为、情感症状以及脑外症状。尽管 Shank3 缺陷会导致多种分子改变，但它们不足以解释这种异基因综合征的所有临床方面。由于对 Shank3 缺陷的整体基因表达变化的研究还不够充分，我们在对照和锂 (Li) 治疗条件下探索了 Shank3Δ11(−/−) 小鼠原代海马细胞的体外转录组，并在体内证实了这些发现。 Shank3Δ11(−/−) 基因型影响整体转录组。值得注意的是，细胞外基质（ECM）和细胞周期转录程序被破坏。因此，在青少年 Shank3Δ11(−/−) 小鼠的海马体中，我们发现胶原蛋白家族的蛋白质和核心细胞周期蛋白下调。 Shank3Δ11(−/−) 细胞的体外 Li 处理对 ECM 和细胞周期基因集具有类似救援的作用。反向 ECM 基因集是网络的一部分，受常见转录因子 (TF) 的调节，例如 cAMP 响应元件结合蛋白 1 (CREB1) 和 β-连环蛋白 (CTNNB1)，它们是已知的突触活性下游效应子和 Li 的靶标。 Shank3Δ11(−/−) 小鼠的海马中这些 TF 的丰度较低和/或低磷酸化，并且可以在体外和体内用 Li 来挽救。我们的研究表明 ECM 区室和细胞周期基因是 Shank3 缺陷病理生理学的新参与者，并且暗示转录调节因子的参与，而转录调节因子可以通过 Li 进行调节。 这项工作支持 Li 作为治疗 PMDS 症状的潜在药物，目前正在进行 III 期研究。