GABAergic Interneuron Dysfunction in Developing Cortical Circuits Underlying Autism Spectrum Disorders

项目摘要 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 环境影响如电活动是GABA能回路成熟的基础。 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续的 神经病理学这项提案的目的是揭示潜在活动的信号通路- 依赖性发展，并评估这一过程中的扰动如何导致异常的大脑功能。 为此，我们将使用小鼠桶皮质作为一个良好建立的模型，用于研究活动依赖性 电路成熟我们将把我们的研究集中在皮层中间神经元，因为我们以前的工作表明， 这些神经元对新生儿的环境扰动非常敏感。在短期内，这 该提案旨在研究特定的中间神经元亚型在调节早期神经元的出现中的作用。 活动模式（目标1）。此外，本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Cacna 1c的作用，Cacna 1c是一种编码 L型钙通道Cav1.2亚基。这个基因的突变与蒂莫西 综合症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导致发育过程中大脑活动异常，并损害成年人的行为 (Aim 3）。 关于成果，我们的工作预期将确定对实现千年发展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， CACNA 1C基因的突变与自闭症、双相情感障碍、精神分裂症和 Timothy综合征可能导致这些患者中经常观察到的行为异常。

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.