Endothelial cell-derived GABA signaling modulates neuronal migration and postnatal behavior

• Published in: Cell research Vol. 28; no. 2; pp. 221 - 248
• Main Authors: Li, Suyan, Kumar T, Peeyush, Joshee, Sampada, Kirschstein, Timo, Subburaju, Sivan, Khalili, Jahan S, Kloepper, Jonas, Du, Chuang, Elkhal, Abdallah, Szabó, Gábor, Jain, Rakesh K, Köhling, Rüdiger, Vasudevan, Anju
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2018; Nature Publishing Group
• Subjects: 631/136/16; 631/378/87; 631/80/84; 631/80/86; Angiogenesis; Animal models; Animals; Anxiety; Autism; Behavior, Animal; Biomedical and Life Sciences; Blood-brain barrier; Cell Biology; Cell culture; Cell migration; Cell Movement; Central nervous system; Cerebral cortex; Cerebral Cortex - blood supply; Cerebral Cortex - cytology; Cerebral Cortex - embryology; Coalescing; Cues; Embryogenesis; Embryonic growth stage; Endothelial cells; Endothelial Cells - metabolism; Epilepsy; Etiology; Female; Forebrain; GABAergic Neurons - physiology; gamma-Aminobutyric Acid - metabolism; Gene Expression Profiling; Guide rails; Information processing; Interneurons; Interneurons - physiology; Life Sciences; Male; Mental depression; Mental disorders; Mice; Mice, Knockout; Mice, Transgenic; Models, Animal; Neurodevelopmental Disorders - etiology; Neurodevelopmental Disorders - physiopathology; Neurogenesis - physiology; Neuronal-glial interactions; Original; original-article; Phenotype; Pregnancy; Radial glial cells; Receptors, GABA-A - physiology; RNA - genetics; Rodents; Schizophrenia; Signal transduction; Signaling; Ventricle; Vesicular Inhibitory Amino Acid Transport Proteins - metabolism; γ-Aminobutyric acid; 氨基丁酸;房间;信号;行为;移植;调制;生后;精神分裂症; blood vessel; endothelial cells; angiogenesis; neuronal migration; GABAergic neurons; brain; GABA signaling
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2017.135

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 （Gabrb3^ATie-Cre and VgatATie2-Cre, we show that partial or complete loss of GABA release from en- dothelial 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 mech- anisms 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.