Cellular Mechanisms of Convergence Among Autism Spectrum Disorder Genes

自闭症谱系障碍基因趋同的细胞机制

• 批准号: 10313952
• 负责人: Andrew D Nelson
• 金额: $ 6.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10313952
• 关键词: ANK2 gene; Action Potentials; Affect; Ankyrins; Apical; Area; Axon; Brain; Calcium; Calcium Channel; Candidate Disease Gene; Cell physiology; Cells; Clathrin; Cognitive; Communication; Data; Dendrites; Dendritic Spines; Electrophysiology (science); Endocytosis; Excitatory Synapse; FMR1; Family; Functional disorder; Gene Expression; General Population; Genes; Genetic; Glutamates; Goals; Image; Impairment; Ion Channel; Lead; Life; Link; Measures; Mediating; Membrane; Modeling; Mus; Neurodevelopmental Disorder; Neurons; Pattern; Phenocopy; Phenotype; Physiological; Prefrontal Cortex; Pyramidal Cells; Ranvier' s Nodes; Scaffolding Protein; Site; Sodium; Sodium Channel; Synapses; Synaptic plasticity; Testing; Translating; Work; autism spectrum disorder; base; brain circuitry; detector; effective therapy; gene discovery; high risk; hippocampal pyramidal neuron; insight; mouse model; new therapeutic target; risk variant; scaffold; social; sodium-binding benzofuran isophthalate; synaptic function; treatment strategy; two-photon; voltage

ABSTRACT Recent progress in genetics has uncovered over 100 genes associated with autism spectrum disorder (ASD). Identifying points of convergence among ASD candidate genes is the next critical step to translate gene discoveries to pathophysiological changes in brain circuitry. One central locus at which ASD risk genes converge are prefrontal cortex (PFC) layer 5 pyramidal neurons. These neurons have specialized dendritic arbors thought to act as coincidence detectors between local inputs on their basal arbors and long-range modulatory inputs on their apical tufts. Thus, pyramidal cell dendrites may be a major locus for synaptic integration. Abnormal dendritic excitability is hypothesized to contribute to the social, cognitive, and communication deficits typically observed in ASD, but how these deficits manifest at the cellular level remains unclear. Here, I propose that deficits in dendritic integration and dendritic excitability are a core cellular phenotype of ASD. Specifically, I will test the central hypothesis that impaired dendritic excitability is a point of convergence across multiple high-confidence ASD risk genes. Our lab has recently identified dendritic impairments in mice haploinsufficient for a top ASD risk gene, Scn2a. Scn2a encodes the voltage-gated sodium channel NaV1.2, which is critical for the backpropagation of action potentials to apical dendrites to regulate synaptic integration, stability, and plasticity. Interestingly, several high-risk ASD genes may interact with Scn2a—either through membrane scaffolding or gene expression—in ways that could also result in impaired dendritic excitability. Ankyrins, for example, are a family of scaffolding proteins known to localize sodium channels to the axon initial segment and nodes of Ranvier, sites of action potential initiation and propagation. Here, we propose that ankyrin-B, the product of the ASD-associated gene ANK2, is the primary ankyrin that localizes Nav1.2 in dendrites. Consistent with a loss of dendritic NaVs, my preliminary data indicate that Ank2+/- and Scn2a+/- pyramidal cells have identical deficits in excitatory synapse function. Upstream of this direct interaction, the ASD risk genes Fmr1 and Tbr1 have been shown to regulate either Scn2a or AnkB expression. As a result, we expect dendritic excitability to be impaired when any of these genes are affected. We will test our hypothesis by pursing three specific aims: Aim 1: To evaluate the effects of Ank2 loss on dendritic sodium channel function and excitability. Aim 2: To investigate convergence of impaired dendritic excitability in mouse models of ASD risk genes. Aim 3: To determine the effects of Scn2a haploinsufficiency on basal versus apical dendritic excitability. This work is expected to reveal whether dendritic excitability is indeed a point of convergence across high-risk ASD genes, and to further determine precisely what aspects of dendritic excitability are most affected in these cases. Our results will have a positive impact because this work will reveal mechanisms that contribute to altered dendritic excitability, which, in turn, may give us greater insight to the pathophysiology of ASD.

抽象的 仿制药的最新进展发现了与自闭症谱系障碍（ASD）相关的100多种基因。 识别ASD候选基因之间的收敛点是翻译基因的下一个关键步骤 发现大脑回路的病理生理变化。 ASD风险基因收敛的一个中心基因座 是前额叶皮层（PFC）第5层锥体神经元。这些神经元有专门的树突状乔木认为 充当本地输入基本乔木和远程调节输入之间的巧合探测器 他们的顶簇。这，锥体细胞树突可能是突触整合的主要基因座。异常树突状 假设兴奋性有助于社会，认知和交流缺陷，通常会观察到 在ASD中，但是这些缺陷如何在细胞水平上表现出来尚不清楚。在这里，我建议缺乏 树突状融合和树突状令人兴奋是ASD的核心细胞表型。具体来说，我将测试 中心假设，即树突状令人兴奋的损害是跨多个高信任的融合点 ASD风险基因。我们的实验室最近确定了小鼠的树突损伤单倍损害，以达到最高的ASD风险 Gene，SCN2A。 SCN2A编码电压门控钠通道NAV1.2，这对于反向传播至关重要 顶端树突的作用潜力调节合成整合，稳定性和可塑性。有趣的是， 几种高风险的ASD基因可能与SCN2A相互作用 - 通过膜脚手架或基因 表达 - 也可能导致树突状兴奋性受损的方式。例如，Ankyrins是一个家庭 已知将钠通道定位于轴突初始段和兰维尔节点的脚手架蛋白 行动潜在的主动性和传播。在这里，我们建议Ankyrin-B，是ASD相关的乘积 基因ANK2是将NAV1.2定位在树突中的主要a金林。与丧失树突状导航一致 我的初步数据表明ANK2 +/-和SCN2A +/-锥体细胞在兴奋性突触中具有相同的定义 功能。在这种直接相互作用的上游，ASD风险基因FMR1和TBR1已显示用于调节 SCN2A或ANKB表达式。结果，我们希望在任何一个中都会损害树突状的兴奋性 基因受到影响。我们将通过追求三个具体目标来检验我们的假设：目标1：评估 树突状钠通道功能和兴奋性上的ANK2损失。目标2：调查受损的收敛性 ASD风险基因的小鼠模型中的树突刺激性。目标3：确定SCN2A的影响 基本与顶端树突状兴奋的单倍不足。预计这项工作将揭示是否树突状 兴奋性确实是跨高危ASD基因收敛的点，并进一步确定什么 在这些情况下，树突状兴奋的各个方面受到最大的影响。我们的结果将产生积极的影响，因为 这项工作将揭示导致树突状兴奋性改变的机制，反过来可能给我们 对ASD的病理生理学的洞察力更大。