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

Anass Agrud, Sivan Subburaju, Pranay Goel, Jun Ren, Ashwin Srinivasan Kumar, Barbara J Caldarone, Wangde Dai, Jesus Chavez, Dai Fukumura, Rakesh K Jain, Robert A Kloner, Anju Vasudevan

Scientific reports 2022 Mar 22

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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 GABAA receptor-GABA signaling from early embryonic stages can directly contribute to the origin of psychiatric disorders. In the GABAA receptor β3 subunit endothelial cell conditional knockout (Gabrb3ECKO) mice, the β3 subunit is deleted selectively from endothelial cells, therefore endothelial GABAA receptors become inactivated and dysfunctional. There is a reduction in vessel densities and increased vessel morphology in the Gabrb3ECKO telencephalon that persists in the adult neocortex. Gabrb3ECKO mice show behavioral deficits such as impaired reciprocal social interactions, communication deficits, heightened anxiety, and depression. Here, we characterize the functional changes in Gabrb3ECKO 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 Gabrb3ECKO mice. The Gabrb3ECKO 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 Gabrb3ECKO 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. © 2022. The Author(s).

Citation

Anass Agrud, Sivan Subburaju, Pranay Goel, Jun Ren, Ashwin Srinivasan Kumar, Barbara J Caldarone, Wangde Dai, Jesus Chavez, Dai Fukumura, Rakesh K Jain, Robert A Kloner, Anju Vasudevan. Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction. Scientific reports. 2022 Mar 22;12(1):4922