Peripheral cyclical expression of GABA-A receptor subunit genes and menstrual cycle affective change: a dimensional, transdiagnostic study

Menstrual cycle affective change (MCAC), including conditions like Premenstrual Dysphoric Disorder (PMDD), is triggered by ovarian hormone fluctuations, but its neurobiological mechanisms remain poorly understood. A leading hypothesis implicates abnormal GABA-A receptor (GABA_AR) subunit regulation in altering sensitivity to neuroactive steroids, a theory difficult to test in humans. We examined peripheral mRNA expression of GABRD, GABRG2, and GABRA5 in a transdiagnostic sample of 112 participants (75 psychiatric outpatients with suicidality; 37 controls) to capture a dimensional range of MCAC severity. Participants provided daily affect ratings and five LH-timed blood samples using PAXgene tubes for RT-PCR analysis. Replicating preclinical findings, GABRG2 expression decreased during the midluteal phase. Critically, individual differences in both person-mean expression and perimenstrual change (AUCi) were correlated with cyclical symptom trajectories. Greater perimenstrual increases or higher average expression were associated with classic luteal-phase worsening of anxiety (GABRG2, GABRA5), irritability (GABRG2), and suicidal ideation (GABRG2, GABRA5, GABRD). However, relative to those with moderate or stable expression, perimenstrual decreases or lower average expression were also linked to cyclical worsening of anxiety and suicidal ideation that emerged around menses and persisted into the follicular phase. Overall, more stable subunit expression was associated with less cyclical symptom change. These findings could be consistent with a loss of homeostatic stability in GABAergic plasticity, rather than a simple unidirectional differences in levels or changes, as a potential correlate of MCAC. Peripheral GABAAR gene expression warrants further investigation, particularly in experimental studies, to determine whether there are causal associations between subunit gene expression and MCAC.