Developmental Dysfunction of Parvalbumin Interneurons in Autism Spectrum Disorder

自闭症谱系障碍中小白蛋白中间神经元的发育障碍

• 批准号: 10475147
• 负责人: Claire Ward
• 金额: $ 4.68万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475147
• 关键词: ASD patient; Address; Affect; Age; Autopsy; Behavior; Brain; Candidate Disease Gene; Cells; Cerebral cortex; Characteristics; Cognition; Cognitive deficits; Communication; Development; Disease model; Electrophysiology (science); Epilepsy; Excision; Functional disorder; GABA Receptor; Genes; Genetic Transcription; Genetic study; Genomics; Goals; Histologic; Histology; Human; Impaired cognition; Impairment; Interneuron function; Interneurons; Link; Mediating; Missense Mutation; Molecular; Mus; Myoepithelial cell; Neurons; Parvalbumins; Patients; Pattern; Perception; Physiology; Play; Regulation; Reporting; Role; Runaway; Sensory; Shapes; Signal Transduction; Slice; Social Interaction; Symptoms; Synapses; Synaptic Transmission; Testing; Visual Cortex; age related; autism spectrum disorder; autistic; behavioral phenotyping; brain tissue; cell type; excitatory neuron; in vitro activity; in vivo; individuals with autism spectrum disorder; inhibitory neuron; insight; molecular marker; mouse genetics; mouse model; neural network; novel; prevent; receptor expression; synaptic function; transcription factor; transcriptomics

Project Summary Recent evidence suggests disruption of GABAergic inhibitory function as a likely mechanism underlying Autism Spectrum Disorders (ASD). In order to function correctly, neural networks must establish precise and stable interconnected circuits. Synaptic refinement mediated by GABAergic inhibitory neurons during development is necessary for the precision of brain function, and thus, developmental disruption of GABAergic inhibitory neurons (also known as interneurons) has the potential to perturb fundamental cortical functions, such as accurate encoding of sensory information and higher-order cognition. One major challenge in exploring GABAergic dysfunction is the diversity of inhibitory interneurons, which can be subdivided into distinct classes with different physiology, synaptic targets, and molecular markers. In the cortex, the largest interneuron class is comprised of fast-spiking basket cells that express parvalbumin (PV) and target the cell bodies of excitatory neurons, providing rapid, powerful inhibition. Dysregulation of PV-interneurons has been suggested as a candidate mechanism underlying autism, but little is known about the mechanistic contribution of PV- interneurons to ASD-related deficits. Selective disruption of PV-interneuron function in the context of ASD in will provide novel insight into specific GABAergic regulation and dysfunction in ASD. Genetic studies of ASD patients have identified Mef2c as a candidate gene. Small de novo deletions in the Mef2c locus, as well as missense mutations, have been reported in several unrelated patients with autistic features. Mef2c is an activity-dependent transcription that plays a role in synaptic function, and an haploinsufficiency mouse model of Mef2c result in behavioral phenotypes characteristic of ASD. The convergence of human studies, Mef2c function, and the ASD-like behaviors phenotypes present in the Mef2c haploinsufficiency mouse model makes Mef2c an excellent candidate gene for addressing the molecular, cellular and circuit dysfunctions underlying altered behavior in ASD. Mef2c is expressed in cortical excitatory neurons and PV-interneurons, however thus far the cell type-specific role of Mef2c for PV-interneuron function and its relation to ASDs remains unknown. Here, we will use combination of approaches that includes mouse genetics, behavior, histology, synaptic physiology, in vivo electrophysiology, and transcriptomic analyses to test the hypotheses that Mef2c signaling shapes PV-interneuron development, and that age-specific Mef2c-related disruptions of PV-interneurons will impair different aspects of synaptic transmission and cortical activity, gaining mechanistic insights into how impaired PV-interneuron dysfunction can contribute towards ASD symptoms.

项目概要 最近的证据表明 GABA 能抑制功能的破坏可能是潜在的机制 自闭症谱系障碍 (ASD)。为了正确运行，神经网络必须建立精确且 稳定的互连电路。 GABA能抑制神经元介导的突触细化 发育对于大脑功能的精确性是必要的，因此，GABAergic 的发育受到破坏 抑制性神经元（也称为中间神经元）有可能扰乱基本的皮质功能，例如 作为感官信息和高阶认知的准确编码。探索中的一大挑战 GABA 能功能障碍是抑制性中间神经元的多样性，可分为不同的类别 具有不同的生理学、突触目标和分子标记。在皮质中，最大的中间神经元类别是 由表达小清蛋白 (PV) 并靶向兴奋性细胞体的快速尖峰篮细胞组成 神经元，提供快速、强大的抑制作用。 PV 中间神经元的失调被认为是 自闭症的候选机制，但人们对PV-的机制贡献知之甚少 中间神经元与 ASD 相关的缺陷。自闭症谱系障碍 (ASD) 中 PV 中间神经元功能的选择性破坏 为自闭症谱系障碍 (ASD) 中特定 GABA 能调节和功能障碍提供新的见解。 ASD 患者的遗传学研究已将 Mef2c 确定为候选基因。小的从头删除 Mef2c 基因座以及错义突变已在几位无关的自闭症患者中报告过 特征。 Mef2c 是一种活性依赖性转录，在突触功能中发挥作用，并且 Mef2c 的单倍体不足小鼠模型导致 ASD 的行为表型特征。这 人类研究、Mef2c 功能以及 Mef2c 中存在的 ASD 样行为表型的融合 单倍体不足小鼠模型使 Mef2c 成为解决分子、细胞 以及自闭症谱系障碍行为改变背后的回路功能障碍。 Mef2c 在皮质兴奋性神经元中表达 和 PV 中间神经元，然而迄今为止，Mef2c 对 PV 中间神经元功能的细胞类型特异性作用及其 与自闭症谱系障碍 (ASD) 的关系仍不清楚。在这里，我们将结合使用包括小鼠遗传学在内的方法， 行为、组织学、突触生理学、体内电生理学和转录组分析来测试 假设 Mef2c 信号传导塑造 PV 中间神经元发育，并且年龄特异性的 Mef2c 相关 PV 中间神经元的破坏将损害突触传递和皮质活动的不同方面，从而获得 关于受损的 PV 中间神经元功能障碍如何导致自闭症谱系障碍 (ASD) 症状的机制见解。