Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction.

Our recent studies uncovered a novel GABA signaling pathway in embryonic forebrain endothelial cells that works independently from neuronal GABA signaling and revealed that disruptions in endothelial GABA receptor-GABA signaling from early embryonic stages can directly contribute to the origin of psychiatric disorders. In the GABA receptor β3 subunit endothelial cell conditional knockout (Gabrb3) mice, the β3 subunit is deleted selectively from endothelial cells, therefore endothelial GABA receptors become inactivated and dysfunctional. There is a reduction in vessel densities and increased vessel morphology in the Gabrb3 telencephalon that persists in the adult neocortex.

NAD-mediated rescue of prenatal forebrain angiogenesis restores postnatal behavior.

Intrinsic defects within blood vessels from the earliest developmental time points can directly contribute to psychiatric disease origin. Here, we show that nicotinamide adenine dinucleotide (NAD), administered during a critical window of prenatal development, in a mouse model with dysfunctional endothelial γ-aminobutyric acid type A (GABA) receptors ( endothelial cell knockout mice), results in a 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 previously unknown transcriptional mechanisms and purinergic receptor signaling.