Molecular and circuitry mechanism underlying autism behaviors in Shank3 mouse models

Shank3小鼠模型孤独症行为的分子和电路机制 摘要： 虽然在确定自闭症谱系个体的遗传缺陷方面取得了重大进展 疾病(ASD)，分子的异质性不能提供关于遗传缺陷是如何导致的机械性见解 在ASD中。有人提出，与ASD密切相关的&gt；100基因中的缺陷集中在几个不同的 分子通路，并参与支持ASD的共享神经回路。要识别潜在的 我们采用RDoC矩阵在基因-分子-电路-行为(GMCB)中建立联系 与SHANK3相关的ASD的轴。~2%的ASD患者存在SHANK3缺陷，其中大多数 常见缺陷(&gt；95%)是整个SHANK3基因缺失。与14个Shank3亚型特异性相反 基因敲除(KO)小鼠，我们通过常规或有条件的方法培育出了一个独特的Shank3 Complete-KO小鼠 外显子4-22的缺失(Δe4-22或e4-22flx)。∆e4-22小鼠表现出健壮的行为，概括了核心 人类与SHANK3缺乏症相关的ASD特征。我们最近生成了一种新的鼠标，带有一个 Shank3中的Hmer 1结合突变(SH3-PL)，使我们能够探索RDoC基质中的机械联系。 在∆e4-22小鼠中，皮质/纹状体突触功能受损，功能连接异常 针刺核(NAC)相关轴。纹状体和皮质特异的Shank3 e4-22flx小鼠和 病毒介导的SHANK3救援表明NAC和大脑皮层回路在社会、工具性和 以及重复的行为。在分子上，Hmer 1-mGluR5支架在纹状体中发生变化，但皮质没有变化，而 Δe4-22小鼠大脑皮质N-甲基-D-天冬氨酸受体减少，纹状体区不减少。我们的中心假设是 由NAC中Hmer 1-mGluR5支架改变引起的Shank3小鼠的社会和重复行为 回路和NMDAR分别在大脑皮层回路发挥作用。这些分子和电路特有的像差 可能代表了一条聚合的分子通路，具有共同的神经回路，构成了 社交的、工具性的和重复的行为。本提案的具体目标是使用RDoC矩阵 作为使用我们的Shank3 Complete-KO和新的SH3PL小鼠分析GMCB轴内机制的指南。 相关性： 这些结果将为了解Hmer 1-mGluR5支架和NMDAR所扮演的角色提供独特的见解 通过建立基因、分子通路和神经回路的汇聚点来实现类似ASD的行为 可能适用于ASD的靶向治疗。

Molecular and circuitry mechanism underlying autism behaviors in Shank3 mouse models ABSTRACT: While there has been significant progress in identifying the genetic defects in individuals with autism spectrum disorders (ASD), the molecular heterogeneity fails to provide mechanistic insights into how genetic defects result in ASD. It has been proposed that defects in >100 genes strongly implicated in ASD converge onto a few distinct molecular pathways and contribute to the shared neural circuits supporting ASD. To identify the underlying mechaniams we adopted the RDoC matrix to establish links within a Gene-Molecule-Circuit-Behavior (GMCB) axis for SHANK3-related ASD. Defects in SHANK3 are found in ~2% of individuals with ASD, and the most common defect (>95%) is deletion of the entire SHANK3 gene. In contrast to the 14 Shank3 isoform-specific knockout (KO) mice, we have generated a unique Shank3 complete-KO mouse by conventional or conditional deletion of exons 4-22 (Δe4-22 or e4-22flox). The ∆e4-22 mice display robust behaviors that recapitulate core features of ASD associated with SHANK3-deficiency in humans. We recently generated a new mouse with a Homer1 binding mutation (SH3-PL) in Shank3 that permits us to probe mechanistic links within the RDoC matrix. In ∆e4-22 mice functions of cortical/striatal synapses are impaired and functional connectivity is abnormal in the nucleus acumens (NAC) -associated axis. Results from striatal- and cortical-specific Shank3 e4-22flox mice and viral-mediated SHANK3 rescue suggest distinct roles for the NAC and cortical circuits in social, instrumental, and repetitive behaviors. Molecularly, Homer1-mGluR5 scaffolds are altered in the striatum but not cortex, while NMDA receptors are reduced in cortex but not striata of Δe4-22 mice. Our central hypothesis is that abnormal social and repetitive behaviors in Shank3 mice are caused by alterations in Homer1-mGluR5 scaffolds in a NAC circuit and in NMDAR functions in a cortical circuit, respectively. These molecular- and circuit-specific aberrations may represent a convergent molecular pathway with shared neural circuits that underlie the abnormalities in social, instrumental, and repetitive behaviors. The specific objective of this proposal is to use the RDoC matrix as guide to analyze mechanisms within a GMCB axis using our Shank3 complete-KO and the new SH3PL mice. RELEVANCE: These results will provide unique insights into the roles that Homer1-mGluR5 scaffolds and NMDARs play in ASD-like behaviors by establishing a convergent point of genes, molecular pathways, and neural circuits that may be amenable to targeted treatments for ASD.