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: 10287483
• 负责人: Claire Ward
• 金额: $ 4.6万
• 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/10287483
• 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.

项目摘要 最近的证据表明，GABA能抑制功能的破坏是可能的机制 自闭症谱系障碍（ASD）。为了正确功能，神经网络必须建立精确的，并且 稳定的互连电路。由GABA能抑制性神经元介导的突触细化 开发对于大脑功能的精确性是必要的，因此，GABA能的发展破坏 抑制性神经元（也称为中间神经元）具有扰动基本皮质功能的潜力 作为感官信息和高阶认知的准确编码。探索的一个主要挑战 GABA能功能障碍是抑制性中间神经元的多样性，可以细分为不同的类别 具有不同的生理学，突触靶标和分子标记。在皮层中，最大的中间神经元类是 由表达白蛋白（PV）的快速加速篮细胞组成，并针对兴​​奋性的细胞体 神经元可提供快速，强大的抑制作用。已建议PV互操神经元的失调作为一种 自闭症的候选机制，但对PV-的机械贡献知之甚少 与ASD相关的赤字的中间神经元。在Will中的ASD上下文中，PV interneuron函数的选择性破坏 对ASD中特定的GABA能调节和功能障碍提供新的见解。 ASD患者的遗传研究已将MEF2C鉴定为候选基因。从头删除 据报道，几名无关自闭症患者的MEF2C基因座以及错义突变 特征。 MEF2C是一个与活动有关的转录，在突触函数中起作用，一个 MEF2C的单倍不足小鼠模型导致ASD的行为表型的特征。这 MEF2C中存在的人类研究，MEF2C功能和类似ASD的行为表型的收敛性 单倍不足鼠标模型使MEF2C成为解决分子细胞的极好的候选基因 和电路功能障碍在ASD中的行为改变了。 MEF2C在皮质兴奋性神经元中表达 但是，到目前为止 与ASD的关系仍然未知。在这里，我们将使用包括鼠标遗传学的方法组合， 行为，组织学，突触生理学，体内电生理学和转录组分析以测试 假设MEF2C信号传导塑造PV-Interneuron的开发，并且与年龄有关的MEF2C相关 PV - 互操神经元的破坏会损害突触传播和皮质活动的不同方面，并获得 关于PV interneuron功能障碍受损的机理见解会导致ASD症状。