Novel Developmental Pathways Underlying Psychiatric Disorders

摘要 中枢神经系统(CNS)通过血管生成获得血管，这是一个对其发育和修复至关重要的过程。我们的发现为血管生成的内在调控提供了新的视角，并强调了血管多样性在脑发育中的重要性。预先形成的血管网络作为新皮质形成的模板。它们在空间和时间上处于战略位置，为指导大脑发育的关键事件提供支持和关键的指导线索。最近，我们的研究在胚胎前脑内皮细胞中发现了一条新的GABA信号通路，该信号通路独立于神经元GABA信号发挥作用。研究表明，胚胎早期内皮GABA信号的中断可能直接导致自闭症、癫痫、精神分裂症、焦虑和抑郁等精神疾病的发生。这种血管GABA信号通路延伸到出生后阶段，增加了复杂性。因此，我们的更新应用将研究出生后内皮细胞GABAA受体-GABA信号组件的关键基本作用机制，对新皮质发育和疾病具有新的意义。它旨在强调迄今尚不清楚的内皮GABA在血管退化和稳定中的作用机制。它探索了一个新的概念，即内皮GABA成分对于出生后大脑发育是不可或缺的，并可以不同地塑造血液流动。这些结果将揭示控制出生后血管生成的基本机制，为发育中的新皮质的细胞和分子格局提供新的视角，并将导致对几种神经精神疾病的理解和治疗具有前所未有的影响的发现。

Abstract The central nervous system (CNS) acquires its vasculature by angiogenesis, a process that is critical for its development and repair. Our findings have offered new perspectives on intrinsic regulation of angiogenesis and highlighted the importance of vascular diversity during brain development. Pre-formed vascular networks act as a template for the formation of the neocortex. They are strategically positioned, spatially and temporally to provide support and critical guidance cues to instruct key events of brain development. Recently, our studies uncovered a novel GABA signaling pathway in embryonic forebrain endothelial cells that works independently from neuronal GABA signaling. It revealed that disruptions in endothelial GABA signaling from early embryonic stages can directly contribute to the origin of psychiatric disorders including autism, epilepsy, schizophrenia, anxiety and depression. This vascular GABA signaling pathway extends into the postnatal phase with added complexities. Therefore, our renewal application will examine the key fundamental mechanisms of action of endothelial GABAA receptor-GABA signaling components during the postnatal period with new significance for neocortical development and disease. It aims at highlighting hitherto unknown mechanisms of endothelial GABA’s role in vascular regression and stabilization. It explores the novel concept that endothelial GABA components are indispensable for postnatal brain development and can differentially shape blood flow. Results will uncover fundamental mechanisms governing postnatal angiogenesis, offer new perspectives on the cellular and molecular landscape of the developing neocortex and will lead to discoveries with unprecedented implications for understanding and treatment of several neuropsychiatric illnesses.