Gamma-amino butyric acid and the A-type receptor suppress decidualization of mouse uterine stromal cells by down-regulating cyclin D3

Uterine decidualization, characterized by stromal cell proliferation and differentiation into polyploid decidual cells, is critical to the establishment of pregnancy in mice, although the mechanism underlying this process remains poorly understood. This study is the first to investigate the expression of gamma-amino butyric acid (GABA) and the GABA A-type receptor p subunit (GABPR) in the early-pregnancy mouse uterus and their roles in decidualization. The expression of GABRP was detected from Day 4 to 8 of pregnancy. The effects of GABA and GABA A-type receptor on cell proliferation and apoptosis were investigated using the Cell Titer 96 (R) AQueous One Solution Cell Proliferation Assay and flow cytometry. The levels of cyclin D3 protein were measured in cultured stromal cells artificially induced to undergo decidualization, and treated with GABA and a GABA A-type receptor agonist or antagonist, respectively, at the same time. mRNA expression of gabrp in implantation sites was lower than that in inter-implanted sites. GABA and GABRP protein were localized in the luminal and glandular epithelium, stromal cells, and decidual cells. In vitro, GABPR protein level was decreased in cultured stromal cells during the decidualization process. The addition of GABA and the GABA A-type receptor agonist Muscimol inhibited stromal cell proliferation, promoted apoptosis, and arrested cells in S-phase, followed by decreased expression of cyclin D3. These results show that in mice, GABA was actively involved in inhibiting stromal cell proliferation and suppresses decidualization progress through GABA A-type receptors by down-regulating cyclin D3 level. Mol. Reprod. Dev. 80: 5969, 2013. (c) 2012 Wiley Periodicals, Inc.