Mechanistic insights into autocrine and paracrine roles of endothelial GABA signaling in the embryonic forebrain.

The developing cerebral cortex uses a complex developmental plan involving angiogenesis, neurogenesis and neuronal migration. Our recent studies have highlighted the importance of endothelial cell secreted GABA signaling in the embryonic forebrain and established novel autonomous links between blood vessels and the origin of neuropsychiatric diseases. A GABA pathway operates in both endothelial cells and GABAergic neurons of the embryonic telencephalon; however, while the neuronal GABA pathway has been extensively studied, little is known about the endothelial GABA pathway. Our recently generated Vgat endothelial cell knockout mouse model that blocks GABA release from endothelial cells, serves as a new tool to study how endothelial GABA signaling shapes angiogenesis and neurovascular interactions during prenatal development. Quantitative gene expression profiling reveals that the endothelial GABA signaling pathway influences genes connected to specific processes like endothelial cell proliferation, differentiation, migration, tight junction formation, vascular sprouting and integrity. It also shows how components of the neuronal GABA pathway, for instance receptor mediated signaling, cell cycle related components and transcription factors are affected in the absence of endothelial GABA release. Taken together, our findings delineate the close relationship between vascular and nervous systems that begin early in embryogenesis establishing their future interactions and interdependence.