Today 1 in 4 people worldwide suffer every year from some form of neuropsychiatric illness. Psychiatric medications act to ease some of the symptoms with no cure, due to lack of mechanistic insights into how these diseases initiate. One factor known to exert extremely broad influence on brain development and network formation is gamma-aminobutyric acid (GABA). Abnormalities in GABAergic neurons and defects in cortical inhibition have been implicated in the etiology of autism spectrum disorders, epilepsy, schizophrenia, anxiety and depression. Given the significance of abnormal early brain development for these serious psychiatric illnesses, GABA-mediated signaling during development by neuronal progenitors/neurons has been extensively studied. Brain development, however, is not limited to neuronal changes but is also supported by concomitant development of its vasculature. After establishment of the periventricular vascular gradient by embryonic day 11, excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons navigate along diverse courses from ventricular zones, radially and tangentially, to adopt final laminar positions and synchronize cortical microcircuits. While radial glia was established as the substrate for radial neuronal migration in the early seventies, our studies have shown that the developing vascular system exquisitely patterned amidst neurons is the substrate for GABAergic neuronal tangential migration. It highlighted the autonomy of periventricular versus pial vascular networks and revealed that they are independently capable of guiding deep versus superficial GABAergic neuronal populations en route to the cortex.
Not only is the periventricular vascular network acting as a physical substrate for the migration of large populations of deep GABAergic neurons in the embryonic telencephalon, but also it holds the key to several novel developmental mechanisms. Many genes tradionally believed to be confined to neurons/interneurons and their precursors were found to be enriched in periventricular endothelial cells when compared to pial endothelial cells or control endothelial cells prepared from midbrain and hindbrain. As a result of this unique gene expression profile in periventricular endothelial cells, when genes were classified according to disease categories, an enrichment was observed in neuropsychiatric disease categories.
Our findings implicate a new cell type – periventricular endothelial cells as being contributory to a wide swath of psychiatric diseases with schizophrenia, epilepsy, mood, bipolar, depressive disorders and autism topping the list. Interestingly, endothelial cell specific deletion of a single GABAA receptor subunit during prenatal development was sufficient to cause behavioral dysfunction similar to psychiatric disease that are characterized by one or more of these core symptoms – impaired social interactions, communication deficits, depression and increased anxiety. Furthermore, elimination of endothelial GABA release during prenatal development affected postnatal developmental milestones and resulted in a model of childhood epilepsy or autism spectrum disorder. Of note, variation in brain endothelial GABA levels was able to contribute to diversity in psychiatric disease symptoms. Overall, these results indicate that multiple pathways in different cell types (endothelial and neuronal) co-exist in patients with psychiatric disease, synergistically inducing the highly complex form of disease; and it is crucial to understand the implication of autonomous pathways within each cell type and how they interact with one another. Our research thus addresses this important problem with the goal of finding effective cures.