The intimate relationship between vascular and nervous systems begins early in embryogenesis delineating their future interactions and interdependence. Based on anatomical location, independent growth patterns and developmental regulation, forebrain/telencephalic blood vessels fall into two categories: pial and periventricular. While the neural tube directs the formation of the pial vessels that envelop it by embryonic day 9 E9), periventricular vessels originate from a basal vessel on the telencephalic floor of the basal ganglia primordium and develop in an orderly, ventral-to-dorsal gradient by E11. A day after the periventricular vascular network is established, GABA neurons, born in defined germinative zones in the ventral telencephalon, migrate tangentially to adopt their specific positions in the developing cortex. Our recent studies reveal that pial and periventricular vascular networks are strategically positioned to provide support as well as critical guidance cues to instruct GABA neuron migration in the embryonic telencephalon. Interestingly, gene expression profiles of periventricular endothelial cells are distinct from pial endothelial cells. The genes expressed in periventricular endothelial cells were enriched in many neuro-psychiatric disease categories like schizophrenia, epilepsy, autism spectrum disorders, mood, depressive and anxiety disorders. Furthermore, our studies uncovered high expression of GABAA receptors on telencephalic endothelial cells signifying that telencephalic angiogenesis has its own intrisic GABA signalling mechanism that in turn modulates GABA neuron migration in vitro. Additionally, since abnormal migration of GABA neurons during brain development as well as defects in GABAA receptor regulation are known to contribute to several neuropyschiatric disorders, our recent findings assume a new significance. Therefore we selectively deleted GABAA receptor Gabrb3 from endothelial cells to investigate its functional significance in vivo. In this application, we will test the central hypothesis that loss of endothelial Gabrb3 affects GABA secretion from endothelial cells and will result in impaired angiogenesis in embryonic telencephalon that persists into the adult forebrain. We will examine whether loss of endothelial Gabrb3 modulates GABA neuronal migration and final distribution in the embryonic forebrain. A morphological analysis will be performed to screen for region and GABA cell type-specific defects in the adult cerebral cortex of Gabrb3 endothelial cell knockout mice. And finally, we will evaluate if loss of this single GABAA receptor, Gabrb3 from endothelial cells is sufficient to cause behavioral dysfunction. Results will illustrate a novel endothelial GABA signalling pathway that works independent of the classical neuronal GABA signalling pathway with far-reaching consequences for brain development and offer new understanding of serious neuropsychiatric disorders such as schizophrenia, epilepsy, autism spectrum disorders, mood and anxiety related disorders.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
