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 ps...

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Published in:	Scientific reports 2022-03, Vol.12 (1), p.4922-4922, Article 4922
Main Authors:	Agrud, Anass, Subburaju, Sivan, Goel, Pranay, Ren, Jun, Kumar, Ashwin Srinivasan, Caldarone, Barbara J, Dai, Wangde, Chavez, Jesus, Fukumura, Dai, Jain, Rakesh K, Kloner, Robert A, Vasudevan, Anju
Format:	Article
Language:	eng
Subjects:	Animals Blood Blood flow Endothelial cells Endothelial Cells - metabolism Erythrocytes Exploratory behavior Forebrain gamma-Aminobutyric Acid - metabolism Hypertension Hypertension - genetics Hypertension - metabolism Mental disorders Mice Mice, Knockout Neocortex Receptors, GABA-A - metabolism Schizophrenia Short term memory Signal transduction Social interactions Telencephalon γ-Aminobutyric acid A receptors
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Summary:	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. Gabrb3 mice show behavioral deficits such as impaired reciprocal social interactions, communication deficits, heightened anxiety, and depression. Here, we characterize the functional changes in Gabrb3 mice by evaluating cortical blood flow, examine the consequences of loss of endothelial Gabrb3 on cardiac tissue, and define more in-depth altered behaviors. Red blood cell velocity and blood flow were increased in the cortical microcirculation of the Gabrb3 mice. The Gabrb3 mice had a reduction in vessel densities in the heart, similar to the brain; exhibited wavy, myocardial fibers, with elongated 'worm-like' nuclei in their cardiac histology, and developed hypertension. Additional alterations in behavioral function were observed in the Gabrb3 mice such as increased spontaneous exploratory activity and rearing in an open field, reduced short term memory, decreased ambulatory activity in CLAMS testing, and altered prepulse inhibition to startle, an important biomarker of psychiatric diseases such as schizophrenia. Our results imply that vascular Gabrb3 is a key player in the brain as well as the heart, and its loss in both organs can lead to concurrent development of psychiatric and cardiac dysfunction.
ISSN:	2045-2322 2045-2322