GABAAR Plasticity during Pregnancy: Relevance to Postpartum Depression

SummaryFluctuating neurosteroid levels over the ovarian cycle modulate neuronal excitability through effects on GABAA receptors (GABAARs). The large increase in progesterone-derived neurosteroids during pregnancy and their precipitous decline at parturition may have considerable effects on GABAARs during pregnancy and postpartum. Here we show a significant decrease in tonic and phasic inhibitions in pregnant mice, mediated by a downregulation of GABAAR δ and γ2 subunits, respectively, which rebounds immediately postpartum. Mice which do not exhibit GABAAR δ subunit regulation throughout pregnancy (Gabrd+/− and Gabrd−/−) exhibit depression-like and abnormal maternal behaviors, resulting in reduced pup survival. These abnormal postpartum behaviors were ameliorated in Gabrd+/− mice by a GABAAR δ-subunit-selective agonist, THIP. We suggest that Gabrd+/− and Gabrd−/− mice constitute a mouse model of postpartum depression that may be useful for evaluating potential therapeutic interventions