Abstract：
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 GABAA 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.
摘要：
雌激素被认为部分地通过调节皮层和海马中的突触传递来调节认知功能。给予17β-雌二醇（E2）可以通过激活G蛋白偶联的雌激素受体1（GPER1）迅速增强海马中的兴奋性突触传递，并促进大鼠外侧内嗅皮质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10nME2给药对II/III层内嗅神经元药理学分离的兴奋性和抑制性突触电流的影响.在出生后第63天（PD）和74天之间对雌性Long-Evans大鼠进行卵巢切除，并植入真皮下E2胶囊以维持E2的持续低水平。在卵巢切除术后7至20天之间获得电生理记录。应用E220分钟不会显着影响AMPA或NMDA受体介导的兴奋性突触电流。然而,GABA受体介导的抑制性突触电流（IPSC）被E2显着降低，并在20分钟的洗脱期恢复至基线水平。在GPER1受体拮抗剂G15存在下阻断GABA介导的IPSC的抑制。GPER1可以调节蛋白激酶A（PKA），但用细胞内KT5720阻断PKA并不能阻止E2诱导的IPSC减少。GPER1还可以刺激细胞外信号调节激酶（ERK），GABAA受体的负调节剂，用PD90859阻断ERK的激活阻止了E2诱导的IPSC的减少。因此，E2可以导致GABA介导的IPSC中GPER1和ERK信号传导介导的快速减少。这提供了一种新机制，通过该机制，E2可以快速调节内嗅层II/III神经元的突触兴奋性，并且还可能导致其他大脑区域的E2和ERK依赖性突触传递改变。
