GABAergic Interneuron Dysfunction in Developing Cortical Circuits Underlying Autism Spectrum Disorders

自闭症谱系障碍下皮质回路发育中的 GABA 能中间神经元功能障碍

基本信息

批准号：
10306380
负责人：
Natalia Vanesa De Marco Garcia
金额：
$ 42.18万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10306380
关键词：
Adult Affect Alleles Apoptosis Behavior Behavioral Bipolar Disorder Brain Calcium Cell Death Cerebral cortex Data Defect Development Disease Electroporation Emergency Situation Ensure Equilibrium Etiology Event Functional disorder Ganglia Genes Genetic Goals Image Impairment Interneurons Knowledge L-Type Calcium Channels Laser Scanning Microscopy Lead Medial Mediating Mus Mutation Neurodevelopmental Disorder Neurons Outcome Output Parvalbumins Patients Pattern Phenotype Process Pyramidal Cells Regulation Research Role Schizophrenia Sensory Shapes Signal Pathway Signal Transduction Slice Somatostatin Source Stimulus Study models Synapses Tactile Techniques Testing Timothy syndrome Vibrissae Work attenuation autism spectrum disorder barrel cortex behavioral impairment brain abnormalities childhood epilepsy clinically relevant critical period excitatory neuron experimental study gamma-Aminobutyric Acid genetic approach high risk in utero in vivo in vivo calcium imaging inhibitory neuron innovation maladaptive behavior mutant neonate neuropathology novel optogenetics postnatal postnatal development programs pup receptor response translational impact two-photon

项目摘要

Project Summary In the cerebral cortex, gamma-aminobutyric acid (GABA)ergic interneurons are the major source of inhibition. Interneuron dysfunction is strongly associated with autism and childhood epilepsy. We demonstrated that environmental influences such as electrical activity are fundamental for the maturation of GABAergic circuits. However, the identity of the activity patterns controlling interneuron development remains poorly understood. The long-term goal of this research is to uncover how early interneuron dysfunction leads to lasting neuropathologies. The objective of this proposal is to reveal the signaling pathways underlying activity- dependent development and to assess how perturbations in this process lead to aberrant brain function. To this end, we will use the murine barrel cortex as a well-established model for the study of activity-dependent circuit maturation. We will focus our studies in cortical interneurons since our previous work indicates that these neurons are exquisitely sensitive to environmental perturbations in the neonate. In the near term, this proposal is aimed at investigating the role of specific interneuron subtypes in regulating the emergence of early activity patterns (Aim 1). In addition, this project will determine the calcium-dependent signaling pathways for the functional maturation of interneuron networks. We will study the role of Cacna1c, a gene encoding for the Cav1.2 subunit of L-type calcium channels. Mutations in this gene are strongly associated with Timothy syndrome and other neurodevelopmental disorders (Aim 2). Finally, we will assess how developmental defects in interneuron number lead to abnormal brain activity during development and impaired behavior in the adult (Aim 3). With respect to the outcomes, our work is expected to identify basic mechanisms fundamental for the emergency of a healthy balance in the number of excitatory and inhibitory neurons. In addition, these results are expected to have a significant translational impact because they will expand our mechanistic knowledge on how mutations in the CACNA1C gene, strongly associated with autism, bipolar disorder, schizophrenia and Timothy syndrome, may lead to behavioral abnormalities frequently observed in these patients.

项目概要在大脑皮层中，γ-氨基丁酸 (GABA) 能中间神经元是抑制的主要来源。中间神经元功能障碍与自闭症和儿童癫痫密切相关。我们证明了电活动等环境影响是 GABA 电路成熟的基础。然而，控制中间神经元发育的活动模式的身份仍然知之甚少。这项研究的长期目标是揭示早期中间神经元功能障碍如何导致持久的神经病理学。该提案的目的是揭示活动背后的信号传导途径 - 依赖性发展并评估该过程中的扰动如何导致异常的大脑功能。为此，我们将使用小鼠桶状皮层作为研究活动依赖性的成熟模型电路成熟。我们将把研究重点放在皮质中间神经元上，因为我们之前的工作表明这些神经元对新生儿的环境扰动非常敏感。短期内，这该提案旨在调查特定中间神经元亚型在调节早期神经元出现中的作用活动模式（目标 1）。此外，该项目将确定钙依赖性信号通路中间神经元网络的功能成熟。我们将研究 Cacna1c 的作用，Cacna1c 是编码 L 型钙通道的 Cav1.2 亚基。该基因的突变与蒂莫西密切相关综合征和其他神经发育障碍（目标 2）。最后，我们将评估发育缺陷如何中间神经元数量的减少会导致发育过程中的大脑活动异常以及成人的行为受损（目标 3）。就成果而言，我们的工作预计将确定对实现这一目标至关重要的基本机制。兴奋性和抑制性神经元数量的健康平衡的紧急情况。此外，这些结果预计将产生重大的转化影响，因为它们将扩展我们的机械知识 CACNA1C 基因突变如何与自闭症、双相情感障碍、精神分裂症和蒂莫西综合症可能会导致这些患者经常观察到的行为异常。