Research Paper Volume 14, Issue 20 pp 8437—8447
Gabrb2 knock-out mice exhibit double-directed PMDD-like symptoms: GABAAR subunits, neurotransmitter metabolism disruption, and allopregnanolone binding
- 1 Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
- 2 Experimental Centre, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
- 3 College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
Received: August 8, 2022 Accepted: October 14, 2022 Published: October 24, 2022
https://doi.org/10.18632/aging.204351How to Cite
Copyright: © 2022 Gao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Premenstrual dysphoric disorder (PMDD) is a severe mood disorder with pathological changes rooted in GABRB2 copy number variation. Here, we aimed to elucidate the gene dose effect and allopregnanolone binding mechanism of Gabrb2 on possible PMDD-like and comorbid phenotypes in knockout mice.
Methods: PMDD-like behaviors of Gabrb2-knockout mice were measured through various tests. Western Blot and ELISA were used to detect changes in the GABAAR subunits and related neurotransmitter changes in mice respectively for the internal mechanism. The response of mice to allopregnanolone (ALLO) was examined through an exogenous ALLO injection, then validated by the patch-clamp technique to elaborate the potential mechanism of ALLO-mediated GABAAR.
Results: Gabrb2-knockout mice displayed changes in anxiety-like and depression-like emotions opposite to PMDD symptoms, changes in social, learning, and memory capacities similar to PMDD symptoms, and pain threshold changes opposite to PMDD symptoms. GABAAR δ subunit expression in the brains of the Gabrb2-knockout mice was significantly higher than that of Wild-type mice (P<0.05). Gabrb2-knockout mice demonstrated neurotransmitter metabolism disturbance of GABA, Glu, acetylcholine, DA, norepinephrine, and epinephrine. Moreover, Gabrb2-knockout mice did not display the expected phenotypic effect after ALLO injection. Relative to WT mice, the knockout of the β2 subunit gene enhanced the agonistic effect of ALLO on GABAA receptors in cortical neuronal cells.
Conclusions: GABAAR β 2 regulates PMDD-like behaviors. The ALLO binding site may not be located on β two subunits, abnormal δ and ε subunit expression in the mouse brain and the disturbance of neurotransmitters may result in ALLO sensitivity.