Developmental Dysfunction of Parvalbumin Interneurons in Autism Spectrum Disorder

项目摘要 最近的证据表明，GABA能抑制功能的破坏可能是 自闭症谱系障碍(ASD)。为了正确运行，神经网络必须建立精确和 稳定的互联电路。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度是必要的，因此，GABA能的发育障碍 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，如 感觉信息的准确编码和更高层次的认知。探索中的一个主要挑战 GABA能功能障碍是抑制性中间神经元的多样性，可细分为不同的类别 有着不同的生理、突触靶标和分子标记。在大脑皮层，最大的中间神经元类别是 由表达小白蛋白(PV)并以兴奋性胞体为靶点的快速刺激性篮子细胞组成 神经元，提供快速、强大的抑制作用。PV中间神经元的调节失调被认为是一种 自闭症的候选机制，但对PV的机制贡献知之甚少 中间神经元与ASD相关的缺陷。遗嘱中ASD背景下PV-中间神经元功能的选择性中断 为ASD中特定的GABA能调节和功能障碍提供新的见解。 对ASD患者的遗传学研究已经确定MEF2C是一个候选基因。中的小段从头删除 MEF2C基因座以及错义突变已在几个无关的自闭症患者中被报道 功能。MEF2C是一种活性依赖的转录，在突触功能中发挥作用，并且 MEF2C单倍体缺陷小鼠模型导致ASD特有的行为表型。这个 人类研究、MEF2C功能和MEF2C中存在的ASD样行为表型的融合 单倍体功能不全小鼠模型使MEF2C成为解决分子、细胞 以及ASD中潜在的行为改变的电路功能障碍。MEF2C在皮质兴奋性神经元中表达 和PV-中间神经元，然而到目前为止，MEF2C对PV-中间神经元功能的细胞类型特异性作用及其 与自闭症的关系仍不清楚。在这里，我们将使用包括老鼠遗传学在内的多种方法的组合， 行为，组织学，突触生理学，体内电生理学，和转录分析，以测试 MEF2C信号塑造PV中间神经元发育的假说，以及特定年龄的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 对受损的PV-中间神经元功能障碍如何导致ASD症状的机械性见解。

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.