Volume 28, No 2, Feb 2018
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 28 Issue 2, February 2018: 221-248 | Open Access
ORIGINAL ARTICLES
Endothelial cell-derived GABA signaling modulates neuronal migration and postnatal behavior
Suyan Li1,2,*, Peeyush Kumar T1,2,*, Sampada Joshee2, Timo Kirschstein3, Sivan Subburaju1,4, Jahan S Khalili5, Jonas Kloepper6, Chuang Du7, Abdallah Elkhal8,9, Gábor Szabó10, Rakesh K Jain6, Rüdiger Köhling3 and Anju Vasudevan1,2
1Department of Psychiatry, Harvard Medical School, Boston, MA 02215, USA;
2Angiogenesis and Brain Development Laboratory, Division of Basic Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA;
3Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Gertrudenstrasse 9, 18057 Rostock, Germany;
4Program in Structural and Molecular Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA;
5Personal Peptides LLC, Houston, TX 77002, USA;
6Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA;
7Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02148, USA;
8Department of Surgery, Harvard Medical School, Boston, MA 02115, USA;
9Division of Transplantation, Brigham and Women's Hospital, 221 Longwood Avenue, EBRC 309, Boston, MA 02115, USA;
10Laboratory of Molecular Biology and Genetics, Department of Gene Technology and Developmental Neurobiology, Institute of Experimental Medicine, 1083 Budapest, Hungary
Correspondence: Anju Vasudevan,(avasudevan@mclean.harvard.edu)
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.
10.1038/cr.2017.135
FULL TEXT | PDF
Browse 1967
