Novel Developmental Pathways Underlying Psychiatric Disorders

摘要 大脑皮层对于整合和处理所需信息至关重要 大多数行为。大脑皮层的正确运作需要协调一致的组装 涉及谷氨酸能投射神经元和 GABA 能中间神经元的电路。的 神经元、轴突侧支和树突的极其精确的层状排列 当神经元从增殖细胞相继迁移时，在胚胎发育过程中出现 脑室区合并成特定的皮质层。虽然放射状胶质细胞被确定为 用于将投射神经元前体迁移至皮质板的基底或导轨 七十年代初期，GABA 能中间神经元迁移的底物是一个缺失的环节。我们的 最近的研究表明，胚胎前脑中预先形成的血管网络是 战略定位为完成艰巨的任务，为 GABA 神经元从大脑皮层下迁移到发育中的大脑皮层。这个 应用程序将详细检查内皮细胞-神经元相互作用的这种新范例 细胞和分子水平。它将通过以下方式阐明新信号机制的重要性 迄今为止，人们认为前脑内皮细胞完全是神经元细胞。它将检查 这些新的发育途径的改变如何扰乱分层血管模式； 扰乱神经元迁移和皮质组织。结果将说明对 大脑皮层回路、血流和产后行为对精神病学具有新的意义 失调。

Abstract The cerebral cortex is essential for integration and processing of information that is required for most behaviors. Correct functioning of the cerebral cortex necessitates the concerted assembly of circuits involving glutamatergic projection neurons and GABAergic interneurons. The exquisitely precise laminar arrangement of neurons, axon collaterals and dendritic processes arises during embryonic development when neurons migrate successively from proliferative ventricular zones to coalesce into specific cortical layers. While radial glia was identified as substrates or guide rails for migration of projection neuron precursors to the cortical plate in the early seventies, the substrate for GABAergic interneuron migration was a missing link. Our recent work has shown that pre-formed vascular networks in the embryonic forebrain are strategically positioned to fulfill the formidable task of providing support and guidance cues to GABA neurons as they migrate from the subpallium to the developing cerebral cortex. This application will examine this novel paradigm of endothelial cell-neuron interactions at detailed cellular and molecular levels. It will elucidate the importance of new signaling mechanisms via forebrain endothelial cells that were hitherto believed to be exclusively neuronal. It will examine how alterations in these novel developmental pathways disturb hierarchical vascular patterns; perturb neuronal migration and cortical organization. Results will illustrate a powerful impact on cerebral cortex circuitry, blood flow and postnatal behavior with new significance for psychiatric disorders.