Person:

Subburaju, Sivan

The cerebral cortex is essential for integration and processing of information that is required for most behaviors. The exquisitely precise laminar organization of the cerebral cortex arises during embryonic development when neurons migrate successively from ventricular zones to coalesce into specific cortical layers. While radial glia act as guide rails for projection neuron migration, pre-formed vascular networks provide support and guidance cues for GABAergic interneuron migration. This study provides novel conceptual and mechanistic insights into this paradigm of vascular-neuronal interactions, revealing new mechanisms of GABA and its receptor-mediated signaling via embryonic forebrain endothelial cells. With the use of two new endothelial cell specific conditional mouse models of the GABA pathway (Gabrb3ΔTie2-Cre and VgatΔTie2-Cre), we show that partial or complete loss of GABA release from endothelial cells during embryogenesis results in vascular defects and impairs long-distance migration and positioning of cortical interneurons. The downstream effects of perturbed endothelial cell-derived GABA signaling are critical, leading to lasting changes to cortical circuits and persistent behavioral deficits. Furthermore, we illustrate new mechanisms of activation of GABA signaling in forebrain endothelial cells that promotes their migration, angiogenesis and acquisition of blood-brain barrier properties. Our findings uncover and elucidate a novel endothelial GABA signaling pathway in the CNS that is distinct from the classical neuronal GABA signaling pathway and shed new light on the etiology and pathophysiology of neuropsychiatric diseases, such as autism spectrum disorders, epilepsy, anxiety, depression and schizophrenia.

Intrinsic defects within blood vessels from the earliest developmental time points can directly contribute to psychiatric disease origin. Our work has shown that pre-formed vascular networks autonomously regulate key events during brain development, such as neurogenesis and neuronal migration. Vascular deficits and abnormalities in blood vessels emerging at prenatal stages will persist in the adult brain with direct consequences for blood flow and behavior. Therefore, rescue of abnormal prenatal angiogenesis is pivotal for the rescue of brain development and is a vital aspect for preventing the origin of psychiatric disease. Here we show for the first time, that nicotinamide adenine dinucleotide (NAD+), administered during a critical window of prenatal development in a pre-clinical model of psychiatric disease, results in synergistic repair of impaired angiogenesis and normalization of brain development, thus preventing the acquisition of abnormal behavioral symptoms. The prenatal NAD+ treatment stimulated extensive cellular and molecular changes in endothelial cells, and restored blood vessel formation, GABAergic neuronal development, and forebrain morphology by recruiting an alternate pathway for cellular repair, via new transcriptional mechanisms and purinergic receptor signaling. It rescued the lost neuro-vascular interactions, by restoring endothelial cell-derived GABA, a valuable guidance cue for the long-distance migration of GABAergic interneurons to their final destination in the embryonic forebrain. This rescue of forebrain angiogenesis in the prenatal period was of a permanent and irreversible nature, and significantly improved blood flow in the adult brain. A multi-faceted behavioral phenotype that included stress, anxiety, depression, sociability and cognition were completely cured in this psychiatric disease model. Our findings illustrate a novel and powerful role for NAD+ in sculpting vascular networks during prenatal brain development that has profound implications for rescuing brain blood flow with long lasting consequences for mental health outcome.