State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 86025, China; Department of Obstetrics and Gynecology, Hangzhou First People׳s Hospital, Hangzhou 860571, China.
Department of Physiology, Nanjing Medical University, Nanjing 86025, China.
Eur Neuropsychopharmacol. 2017 Aug;27(8):759-772. doi: 10.1016/j.euroneuro.2017.05.010. Epub 2017 Jun 13.
Postpartum estrogen (E2) withdrawal is known to be a particularly vulnerable time for depressive symptoms. In this study, ovariectomized (OVX) mice were treated with co-administration of estradiol benzoate and progesterone (E2/P4) followed by administration of E2 alone (E2) and a subsequent E2 withdrawal (EW) to mimic the hormonal changes during pregnancy and postpartum. The objective of this study was to investigate the influence of E2 withdrawal after hormone-simulated pregnancy on synaptic function and plasticity in basolateral amygdala complex (BLA). In comparison to control mice, EW mice spent less time in the central portion of open-field test and open arms of elevated plus-maze. Excitatory postsynaptic potentials (EPSPs) slopes at external capsule BLA synapse were reduced in E2/P4-mice, recovered in E2-mice, and increased in EW-mice. EW-mice showed a significant increase in duration of EPSPs and paired-pulse inhibition (PPI) with multi-spike responses of EPSPs and impairment of long-term depression (LTD) induction, which were corrected by GABAR agonist muscimol. Levels of estrogen receptor (ER) GPR30, ERα and ERβ expression in BLA of EW-mice were lower than those in control mice. The bath-application of GPR30 agonist G-1 in BLA of EW-mice recovered the GABAR-mediated inhibition and LTD indication, but ERβ agonist DPN or ERα agonist PPT could not. A single BLA-injection of G-1 rather than DPN or PPT in EW-mice could partially relieve the anxiety-like behaviors. The results indicate that postpartum E2 withdrawal causes dysfunction of GABAR-mediated inhibition in the BLA through reducing GPR30 expression, which impairs LTD induction and causes anxiety-like behaviors.
产后雌激素（E2）撤退被认为是抑郁症状特别脆弱的时期。在这项研究中，去卵巢（OVX）小鼠接受苯甲酸雌二醇和孕酮（E2/P4）联合治疗，然后单独给予 E2（E2）和随后的 E2 撤退（EW），以模拟妊娠和产后期间的激素变化。本研究的目的是研究激素模拟妊娠后 E2 撤退对基底外侧杏仁核复合体（BLA）突触功能和可塑性的影响。与对照小鼠相比，EW 小鼠在旷场测试的中央部分和高架十字迷宫的开放臂中花费的时间更少。在外部囊泡 BLA 突触处，E2/P4 小鼠的兴奋性突触后电位（EPSP）斜率降低，E2 小鼠恢复，EW 小鼠增加。EW 小鼠的 EPSP 持续时间和成对脉冲抑制（PPI）显著增加，具有 EPSP 的多尖峰反应和长时程抑制（LTD）诱导受损，这些受损可通过 GABA 受体激动剂 muscimol 纠正。EW 小鼠 BLA 中的雌激素受体（ER）GPR30、ERα 和 ERβ 表达水平低于对照小鼠。在 EW 小鼠的 BLA 中应用 GPR30 激动剂 G-1 可恢复 GABA 介导的抑制和 LTD 指示，但 ERβ 激动剂 DPN 或 ERα 激动剂 PPT 则不能。在 EW 小鼠的 BLA 中单次注射 G-1 而不是 DPN 或 PPT 可部分缓解焦虑样行为。结果表明，产后 E2 撤退通过降低 GPR30 表达导致 BLA 中 GABA 介导的抑制功能障碍，从而损害 LTD 诱导并引起焦虑样行为。
