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: 10687877
• 负责人: Andrew D Nelson
• 金额: $ 7.63万
• 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/10687877
• 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; Laboratory Finding; Link; Measures; Mediating; Membrane; Modeling; Mus; Neurodevelopmental Disorder; Neurons; Pattern; Phenocopy; Phenotype; Physiological; Prefrontal Cortex; Pyramidal Cells; Ranvier' s Nodes; SCN2A protein; Scaffolding Protein; Site; Sodium; Sodium Channel; Synapses; Synaptic plasticity; Testing; Translating; Work; autism spectrum disorder; brain circuitry; detector; effective therapy; gene discovery; high risk; hippocampal pyramidal neuron; insight; mouse model; new therapeutic target; novel therapeutic intervention; risk variant; scaffold; social; sodium-binding benzofuran isophthalate; synaptic function; 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.

摘要