Abstract
Premenstrual dysphoric disorder (PMDD) has been hypothesized to be related to an altered sensitivity of the γ-aminobutyric acid type A (GABA(A)) receptor to progesterone-derived neurosteroids. GABA(A) receptor sensitivity to neurosteroid-modulation is dependent on its subunit composition. In the present study, we used quantitative reverse transcription polymerase chain reactions (RT-qPCR) to compare messenger ribonucleic acid (mRNA) expression of GABA(A) receptor subunits in peripheral mononuclear cells (PBMCs) across the menstrual cycle in 29 women with PMDD and 27 controls. We related mRNA subunit expression to serum levels of neurosteroids and to functional activation of the amygdala, a key brain region involved in emotion generation, measured using functional magnetic resonance imaging (fMRI). Women with PMDD had lower mRNA expression of the delta GABA(A) receptor subunit during the symptomatic, luteal phase (compared to the asymptomatic, follicular phase) of the menstrual cycle. Lower delta mRNA expression was related to higher amygdala activation in PMDD women. GABA(A) receptors incorporating the delta subunit are especially sensitive to neurosteroid modulation. It is possible that the mood symptoms of PMDD are mediated by an inability to effectively adjust the expression of this receptor type in response to neurosteroid fluctuations, leading to dysregulation GABAergic tone and increased activity in emotion-generating brain circuits.