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

• 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
• 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

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.

项目摘要 在大脑皮层，γ-氨基丁酸(GABA)能中间神经元是抑制的主要来源。 神经元间功能障碍与自闭症和儿童癫痫密切相关。我们证明了这一点 环境的影响，如电活动，是GABA能电路成熟的基础。 然而，控制神经元间发育的活动模式的一致性仍然知之甚少。 这项研究的长期目标是揭示早期中间神经元功能障碍是如何导致持久的 神经病理学。这项提议的目标是揭示潜在活动的信号通路-- 并评估这一过程中的扰动是如何导致大脑功能异常的。 为此，我们将使用小鼠桶状皮质作为研究活动依赖的成熟模型。 电路成熟。我们将重点研究皮质中间神经元，因为我们之前的工作表明 这些神经元对新生儿的环境干扰非常敏感。在短期内，这一点 该提案旨在研究特定的中间神经元亚型在调节早期脑缺血发作中的作用。 活动模式(目标1)。此外，该项目还将确定钙依赖的信号通路 神经元间网络的功能成熟。我们将研究CACNA1C的作用，CACNA1C是编码 Cav1.2亚基为L型钙通道。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是如何 中间神经元数量减少导致成人发育过程中脑活动异常和行为受损 (目标3)。 关于结果，我们的工作预计将确定基本机制，为 兴奋性神经元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 预计将产生重大的翻译影响，因为它们将扩展我们对 CACNA1C基因突变与自闭症、双相情感障碍、精神分裂症和 Timothy综合征，可能会导致这些患者经常观察到的行为异常。