A Circuit Mechanism for the Development of Cortico-cortical Connectivity

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。我们将把研究集中在表面电路上，因为我们之前的工作表明，这些 神经回路对新生儿的环境干扰非常敏感。在短期内，这项提议 旨在研究特定的中间神经元亚型在调节长程突起中的作用 连通性(目标1)。此外，该项目将确定GABA能输入对功能的作用 锥体网络的成熟。我们将研究GABRB3的作用，GABRB3是一种编码β3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(AIM 2)。 最后，我们将评估早期GABA能信号的发育缺陷如何导致大脑异常活动 在发育过程中的皮质-皮质通路(目标3)。 关于结果，我们的工作预计将确定基本机制，为 健康的E/I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关于GABRB3基因突变如何导致 到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.