NAD+ Mediated Rescue of Prenatal Forebrain Angiogenesis Restores Postnatal Behavior

Abstract

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.