A Circuit Mechanism for the Development of Cortico-cortical Connectivity

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- 依赖性发育并评估这一过程中的干扰如何导致大脑功能异常。 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表面电路，因为我们以前的工作表明，这些 新生儿的神经回路对环境的扰动非常敏感。从长远来看，这一建议 目的是研究特定的中间神经元亚型在调节长距离神经元的出现中的作用。 连通性（目标1）。此外，本项目将确定GABA能输入对功能性 金字塔网络的成熟。我们将研究Gabrb 3的作用，Gabrb 3是一种编码β 3亚基的基因， GABAA频道该基因的突变与Angelman综合征和ASD密切相关（目的2）。 最后，我们将评估早期GABA能信号的发育缺陷如何导致异常的大脑活动 在发育过程中的皮质-皮质通路（目的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， 健康的E/I平衡。此外，这些结果预计将有重大的翻译 影响，因为它们将扩大我们对GABRB 3基因突变如何导致 ASD患者中常见的行为异常。

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 superficial circuits since our previous work indicates that these circuits 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 long range connectivity (Aim 1). In addition, this project will determine the role of GABAergic inputs for the functional maturation of pyramidal networks. We will study the role of Gabrb3, a gene encoding for the beta3 subunit of GABAA channel. Mutations in this gene are strongly associated with Angelman syndrome and ASD (Aim 2). Finally, we will assess how developmental defects in early GABAergic signaling lead to abnormal brain activity in cortico-cortical pathways during development (Aim 3). With respect to the outcomes, our work is expected to identify basic mechanisms fundamental for the emergency of a healthy E/I balance. In addition, these results are expected to have a significant translational impact because they will expand our mechanistic knowledge on how mutations in the GABRB3 gene may lead to behavioral abnormalities frequently observed in ASD patients.