Novel Developmental Pathways Underlying Psychiatric Disorders

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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.