Neural Mechanism for the assembly of GABAergic in the cerebral cortex

项目摘要 γ-氨基丁酸（GABA）能中间神经元的功能障碍与神经系统疾病密切相关。 包括癫痫、精神分裂症和自闭症谱系障碍的疾病。尽管最近的证据表明 强调了这些神经元的令人困惑的亚型多样性，这一概念表明， 亚型功能导致皮质回路形成缺陷，并伴有持续的功能缺陷， 详细探索。这项研究的长期目标是揭示早期的中间神经元功能障碍是如何发生的。 出生后大脑的发育导致持久的神经病理学。这项提案的目的是揭示 特定中间神经元群在围产期发育关键窗口期的活动如何形成 主要感觉依赖行为的基础电路。 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I层中间神经元亚型在调节皮层神经元出现中的作用。 列（目标1）。此外，该项目将确定LI中间神经元在出现中的作用。 半球间回路(Aim 2）。最后，我们将评估早期LI中间神经元的发育缺陷是如何发生的。 功能导致成人大脑活动异常和感觉统合受损（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， 健康的兴奋/抑制平衡的紧急情况。此外，这些结果预计将有一个 重要的翻译影响，因为它们将扩展我们关于早期中间神经元如何 功能障碍可能导致ASD患者中经常观察到的行为异常。

Project Summary Dysfunction of gamma-aminobutyric acid (GABA)ergic interneurons is strongly associated with neurological disorders including epilepsy, schizophrenia and autism spectrum disorders. Although recent evidence highlights bewildering subtype diversity of these neurons, the notion that developmental perturbations in subtype function cause defects in the formation of cortical circuits with lasting functional deficits has not been explored in detail. The long-term goal of this research is to uncover how early interneuron dysfunction in the developing postnatal brain leads to lasting neurological pathologies. The objective of this proposal is to reveal how the activity of specific interneuron populations during critical windows of perinatal development shape circuits underlying primary sensory-dependent behavior. 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 layer I interneuron subtypes in regulating the emergence of cortical columns (Aim 1). In addition, this project will determine the role of LI interneurons in the emergence of interhemispheric circuits. (Aim 2). Finally, we will assess how developmental defects in early LI interneuron function lead to abnormal brain activity and impaired sensory integration 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 excitatory/inhibitory balance. In addition, these results are expected to have a significant translational impact because they will expand our mechanistic knowledge on how early interneuron dysfunction may lead to behavioral abnormalities frequently observed in ASD patients.