Molecular and circuitry mechanism underlying autism behaviors in Shank3 mouse models

Shank3小鼠模型中自闭症行为的分子和电路机制

• 批准号: 10533806
• 负责人: YONG-HUI JIANG
• 金额: $ 61.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533806
• 关键词: Adopted; Affect; Agonist; Area; Attenuated; Behavior; Binding; Brain; Brain region; Cell Nucleus; Complex; Corpus striatum structure; Defect; Disease model; Exons; Functional disorder; Genes; Heterogeneity; Homer 1; Human; Impairment; Injections; Knock-out; Knockout Mice; Link; Mediating; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; N-Methyl-D-Aspartate Receptors; Neurons; Operant Conditioning; Pathway interactions; Play; Positive Valence; Prosencephalon; Protein Isoforms; Reporting; Reproducibility; Research Domain Criteria; Role; Signal Transduction; Social Behavior; Social Processes; Synapses; System; Testing; Transcriptional Regulation; Viral; autism spectrum disorder; excitatory neuron; frontal lobe; in vivo; individuals with autism spectrum disorder; innovation; insight; mouse model; multidisciplinary; mutant mouse model; neural circuit; pharmacologic; receptor function; repetitive behavior; response; scaffold; social; synaptic function

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.

Shank 3小鼠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， 尽管分子异质性不能提供遗传缺陷如何导致 在ASD已经提出，在ASD中强烈涉及的>100个基因中的缺陷会聚到几个不同的基因中。 分子通路，并有助于支持ASD的共享神经回路。识别潜在的 我们采用RDoC矩阵来建立基因-分子-电路-行为（GMCB）内的链接 轴为SHANK 3相关ASD。SHANK 3缺陷在约2%的ASD患者中发现， 常见的缺陷（>95%）是整个SHANK 3基因的缺失。与14种Shank 3亚型特异性 敲除（KO）小鼠，我们通过常规或条件性产生了独特的Shank 3完全KO小鼠 外显子4-22缺失（Δe4-22或e4- 22 flox）。E4-22小鼠表现出强大的行为， 与人类SHANK 3缺陷相关的ASD特征。我们最近生成了一个新的鼠标， Homer 1结合突变（SH 3-PL）在Shank 3，使我们能够探测RDoC矩阵内的机制链接。 在E4-22小鼠中，皮层/纹状体突触的功能受损，并且在皮层/纹状体突触中功能连接异常。 尖核（NAC）相关轴。来自纹状体和皮质特异性Shank 3 e4- 22 flox小鼠的结果， 病毒介导的SHANK 3拯救表明NAC和皮质回路在社交，工具， 重复的行为。分子上，Homer 1-mGluR 5支架在纹状体而不是皮质中改变， NMDA受体在Δe4-22小鼠的皮质中减少，但不在纹状体中。我们的核心假设是 Shank 3小鼠的社会和重复行为是由NAC中Homer 1-mGluR 5支架的改变引起的。 回路和NMDAR功能分别在皮层回路中。这些分子和电路特异性畸变 可能代表了一个会聚的分子通路，具有共同的神经回路，这些神经回路是异常的基础， 社会性、工具性和重复性行为。本提案的具体目标是使用RDoC矩阵 作为使用我们的Shank 3完全KO和新的SH 3 PL小鼠分析GMCB轴内机制的指导。 相关性： 这些结果将为Homer 1-mGluR 5支架和NMDARs在细胞凋亡中的作用提供独特的见解。 通过建立一个基因、分子通路和神经回路的汇聚点， 可能适用于ASD的靶向治疗。