Gabrb2 knock-out mice exhibit double-directed PMDD-like symptoms: GABAAR subunits, neurotransmitter metabolism disruption, and allopregnanolone binding

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 Gabrb2knockout 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.

Rutin Treats Perimenopausal Depression Rats through Allopregnanolone Mediated mRNA Expression of Gabra4, Gabrb2 in the Prefrontal Cortex

“…GABAR β2 subunit is associated with neuropsychiatric disorders including bipolar disorder, epilepsy, autism spectrum disorder, Alzheimer's disease, depression, and premenstrual dysphoric disorder [34]. Compared to wild-type mice, Gabrb2 knockout mice exhibit lower levels of depression [35,36]. In comparison to normal young mice, perimenopausal mice exhibit a reduced mRNA expression of GABAAR β2 in the prefrontal cortex [37].…”

Factors Associated with Premenstrual Syndrome among Nursing Students Based on the Theory of Unpleasant Symptoms

“…Although the etiology of PMS has not yet been fully identified, it seems that physiological, psychological and situational factors are interrelated, and that changes in neurotransmitters [23,24], psychological factors [25], stress, and hormones [26,27] are probably the primary contributors to the symptoms [28,29]. Nevertheless, few studies have been conducted to comprehensively explain PMS in nursing students based on a theoretical model.…”

“…Consequently, recognizing and understanding factors associated with PMS are critical to establishing a customized management strategy that can alleviate its symptoms. This study was therefore designed to explain PMS in nursing students based on TOUS theory [30,39], which attributes symptom experience to various factors that influence symptoms, and to provide a comprehensive understanding of how physiological factors (i.e., menstrual pain intensity during clinical practice [28,40,41] and sleep quality [36,42]), psychological factors (i.e., neuroticism [43] and stress [44][45][46]), and situational factors (i.e., attitudes towards menstruation [47][48][49] and sex role stereotypes [50,51]) influence PMS in female college nursing students.…”