Premium
GABA A Receptor Gamma 3 is a New Candidate Gene for Cardiovascular and Behavioral Disorders
Author(s) -
XIA JIXIANG,
Batchu Sri,
Donlon Kathy,
Murashev Arkady,
Korshunov Vyacheslav
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.665.4
Subject(s) - locus (genetics) , gabaa receptor , biology , receptor , gene knockin , candidate gene , gene targeting , gene , human brain , microbiology and biotechnology , genetics , neuroscience
We previously discovered a significant locus on mouse chromosome (chr) 7 that controls elevated heart rate in a genetic cross between C3HeB and SJL mice. Association mapping within the locus revealed three subunits of gamma‐aminobutyric acid (GABA) A receptors. The mouse chr7 locus is syntenic to human chr15q locus and is important for mental disorders as well as heart rate variation. The goal of this study was to further investigate the GABAA receptors as candidate genes in the regulation of the cardiovascular system. First, we evaluated expression profiles of the candidate genes in several organs between C3HeB and SJL strains. There was higher mRNA expression of all three GABAA receptors in mouse brain compared to other organs in both strains. We found that alpha5 (~14‐fold) and gamma3 (~5‐fold) were significantly higher in brains from C3HeB compared to SJL mice. In addition, gamma3 mRNA levels were greater in the C3HeB hearts (~20‐fold). Western blot analyses of brain and heart confirmed higher expression of the gamma3 protein in C3HeB versus SJL mice. We genetically targeted the gamma3 gene by using a knockout first and promoter driven reporter tag strategy. Mice with positive alleles for gamma3 showed persistent beta‐galactosidase staining in the brain at embryonic days E12.5 and E15.5. In summary, GABAA gamma3 receptor is a strong candidate gene for elevated heart rate within the mouse chr7 locus. We developed a new mouse model with conditional potential that will allow us to investigate contribution of GABAA gamma3 receptor in cardiovascular and behavioral disorders.