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

基本信息

批准号：
10094257
负责人：
YONG-HUI JIANG
金额：
$ 60.21万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10094257
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 Pharmacology 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 receptor function repetitive behavior response scaffold social synaptic function

项目摘要

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.

Shank3小鼠模型中自闭症行为的分子和电路机制抽象的：虽然在识别自闭症谱系个体的遗传缺陷方面取得了重大进展疾病（ASD），分子异质性无法提供遗传缺陷如何产生的机制见解有人提出，与 ASD 密切相关的 >100 个基因的缺陷集中在几个不同的基因上。分子途径并有助于支持 ASD 的共享神经回路。我们采用 RDoC 矩阵在基因-分子-电路-行为 (GMCB) 内建立链接 SHANK3 相关 ASD 轴存在约 2% 的 ASD 患者，且最多。常见缺陷 (>95%) 是整个 SHANK3 基因的缺失，与 14 Shank3 亚型特异性不同。基因敲除（KO）小鼠，我们通过常规或条件条件产生了独特的Shank3完全KO小鼠外显子 4-22（Δe4-22 或 e4-22flox）的删除 Δe4-22 小鼠表现出重演核心的稳健行为。我们最近培育了一种与人类 SHANK3 缺陷相关的自闭症谱系障碍 (ASD) 特征的新小鼠。 Shank3 中的 Homer1 结合突变 (SH3-PL) 使我们能够探测 RDoC 矩阵内的机制联系。在 Δe4-22 小鼠中，皮质/纹状体突触的功能受损，并且功能连接异常尖核 (NAC) 相关轴的结果来自纹状体和皮质特异性 Shank3 e4-22flox 小鼠和病毒介导的 SHANK3 拯救表明 NAC 和皮质回路在社交、工具、从分子角度来看，Homer1-mGluR5 支架在纹状体中发生了改变，但皮层中没有改变。 Δe4-22 小鼠的皮质中 NMDA 受体减少，但纹状体中没有减少。我们的中心假设是异常。 Shank3 小鼠的社交和重复行为是由 NAC 中 Homer1-mGluR5 支架的改变引起的电路和 NMDAR 分别在皮质电路中发挥作用。可能代表了具有共享神经回路的会聚分子途径，这是异常的基础该提案的具体目标是使用 RDoC 矩阵。作为使用我们的 Shank3 完全 KO 和新的 SH3PL 小鼠分析 GMCB 轴内机制的指南。关联：这些结果将为 Homer1-mGluR5 支架和 NMDAR 在通过建立基因、分子途径和神经回路的汇聚点来实现类似 ASD 的行为可能适合 ASD 的靶向治疗。