Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Québec, Canada.
Hippocampus. 2024 Sep;34(9):454-463. doi: 10.1002/hipo.23621. Epub 2024 Jun 21.
Estrogens are believed to modulate cognitive functions in part through the modulation of synaptic transmission in the cortex and hippocampus. Administration of 17β-estradiol (E2) can rapidly enhance excitatory synaptic transmission in the hippocampus and facilitate excitatory synaptic transmission in rat lateral entorhinal cortex via activation of the G protein-coupled estrogen receptor-1 (GPER1). To assess the mechanisms through which GPER1 activation facilitates synaptic transmission, we assessed the effects of acute 10 nM E2 administration on pharmacologically isolated evoked excitatory and inhibitory synaptic currents in layer II/III entorhinal neurons. Female Long-Evans rats were ovariectomized between postnatal day (PD) 63 and 74 and implanted with a subdermal E2 capsule to maintain continuous low levels of E2. Electrophysiological recordings were obtained between 7 and 20 days after ovariectomy. Application of E2 for 20 min did not significantly affect AMPA or NMDA receptor-mediated excitatory synaptic currents. However, GABA receptor-mediated inhibitory synaptic currents (IPSCs) were markedly reduced by E2 and returned towards baseline levels during the 20-min washout period. The inhibition of GABA-mediated IPSCs was blocked in the presence of the GPER1 receptor antagonist G15. GPER1 can modulate protein kinase A (PKA), but blocking PKA with intracellular KT5720 did not prevent the E2-induced reduction in IPSCs. GPER1 can also stimulate extracellular signal-regulated kinase (ERK), a negative modulator of GABA receptors, and blocking activation of ERK with PD90859 prevented the E2-induced reduction of IPSCs. E2 can therefore result in a rapid GPER1 and ERK signaling-mediated reduction in GABA-mediated IPSCs. This provides a novel mechanism through which E2 can rapidly modulate synaptic excitability in entorhinal layer II/III neurons and may also contribute to E2 and ERK-dependent alterations in synaptic transmission in other brain areas.
雌激素被认为通过调节皮质和海马中的突触传递来调节认知功能。17β-雌二醇（E2）的给药可以通过激活 G 蛋白偶联雌激素受体-1（GPER1）快速增强海马中的兴奋性突触传递，并促进大鼠外侧内嗅皮层中的兴奋性突触传递。为了评估 GPER1 激活促进突触传递的机制，我们评估了急性 10 nM E2 给药对 II/III 层内嗅神经元中药理学分离的诱发兴奋性和抑制性突触电流的影响。雌性 Long-Evans 大鼠在产后第 63 天至 74 天之间进行卵巢切除术，并植入皮下 E2 胶囊以维持持续的低水平 E2。在卵巢切除后 7 至 20 天进行电生理记录。E2 给药 20 分钟不会显著影响 AMPA 或 NMDA 受体介导的兴奋性突触电流。然而，E2 显著抑制 GABA 受体介导的抑制性突触电流（IPSCs），并在 20 分钟洗脱期间恢复到基线水平。在存在 GPER1 受体拮抗剂 G15 的情况下，GABA 介导的 IPSCs 抑制被阻断。GPER1 可以调节蛋白激酶 A（PKA），但用细胞内 KT5720 阻断 PKA 并不能防止 E2 诱导的 IPSCs 减少。GPER1 还可以刺激细胞外信号调节激酶（ERK），GABA 受体的负调节剂，并用 PD90859 阻断 ERK 激活可防止 E2 诱导的 IPSCs 减少。因此，E2 可以导致快速的 GPER1 和 ERK 信号转导介导的 GABA 介导的 IPSCs 减少。这提供了一种新的机制，通过该机制，E2 可以快速调节内嗅皮层 II/III 神经元中的突触兴奋性，并且也可能有助于 E2 和 ERK 依赖性改变其他脑区的突触传递。
