Oberlander Joseph G, Woolley Catherine S
Department of Neurobiology, Northwestern University, Evanston, Illinois 60208.
Department of Neurobiology, Northwestern University, Evanston, Illinois 60208
J Neurosci. 2016 Mar 2;36(9):2677-90. doi: 10.1523/JNEUROSCI.4437-15.2016.
Estradiol (E2) acutely potentiates glutamatergic synaptic transmission in the hippocampus of both male and female rats. Here, we investigated whether E2-induced synaptic potentiation occurs via presynaptic and/or postsynaptic mechanisms and which estrogen receptors (ERs) mediate E2's effects in each sex. Whole-cell voltage-clamp recordings of mEPSCs in CA1 pyramidal neurons showed that E2 increases both mEPSC frequency and amplitude within minutes, but often in different cells. This indicated that both presynaptic and postsynaptic mechanisms are involved, but that they occur largely at different synapses. Two-photon (2p) glutamate uncaging at individual dendritic spines showed that E2 increases the amplitude of uncaging-evoked EPSCs (2pEPSCs) and calcium transients (2pCaTs) at a subset of spines on a dendrite, demonstrating synapse specificity of E2's postsynaptic effects. All of these results were essentially the same in males and females. However, additional experiments using ER-selective agonists indicated sex differences in the mechanisms underlying E2-induced potentiation. In males, an ERβ agonist mimicked the postsynaptic effects of E2 to increase mEPSC, 2pEPSC, and 2pCaT amplitude, whereas in females, these effects were mimicked by an agonist of G protein-coupled ER-1. The presynaptic effect of E2, increased mEPSC frequency, was mimicked by an ERα agonist in males, whereas in females, an ERβ agonist increased mEPSC frequency. Thus, E2 acutely potentiates glutamatergic synapses similarly in both sexes, but distinct ER subtypes mediate the presynaptic and postsynaptic aspects of potentiation in each sex. This indicates a latent sex difference in which different molecular mechanisms converge to the same functional endpoint in males versus females.
Some sex differences in the brain may be latent differences, in which the same functional endpoint is achieved through distinct underlying mechanisms in males versus females. Here we report a latent sex difference in molecular regulation of excitatory synapses in the hippocampus. The steroid 17β-estradiol is known to acutely potentiate glutamatergic synaptic transmission in both sexes. We find that this occurs through a combination of increased presynaptic glutamate release probability and increased postsynaptic sensitivity to glutamate in both sexes, but that distinct estrogen receptor subtypes underlie each aspect of potentiation in each sex. These results indicate that therapeutics targeting a specific estrogen receptor subtype or its downstream signaling would likely affect synaptic transmission differently in the hippocampus of each sex.
雌二醇（E2）能迅速增强雄性和雌性大鼠海马体中的谷氨酸能突触传递。在此，我们研究了E2诱导的突触增强是否通过突触前和/或突触后机制发生，以及哪种雌激素受体（ERs）介导E2对每种性别的作用。对CA1锥体神经元微小兴奋性突触后电流（mEPSCs）进行全细胞电压钳记录显示，E2在数分钟内增加了mEPSC的频率和幅度，但通常在不同细胞中出现这种情况。这表明突触前和突触后机制均有涉及，但它们主要发生在不同的突触处。在单个树突棘处进行双光子（2p）谷氨酸光解笼实验表明，E2增加了树突上一部分棘突处光解笼诱发的兴奋性突触后电流（2pEPSCs）和钙瞬变（2pCaTs）的幅度，证明了E2突触后效应的突触特异性。所有这些结果在雄性和雌性中基本相同。然而，使用ER选择性激动剂的额外实验表明，E2诱导增强作用的潜在机制存在性别差异。在雄性中，一种ERβ激动剂模拟了E2的突触后效应，增加了mEPSC、2pEPSC和2pCaT的幅度，而在雌性中，这些效应由G蛋白偶联的ER-1激动剂模拟。E2的突触前效应，即mEPSC频率增加，在雄性中由ERα激动剂模拟，而在雌性中，一种ERβ激动剂增加了mEPSC频率。因此，E2在两性中均能迅速增强谷氨酸能突触，但不同的ER亚型介导了每种性别中增强作用的突触前和突触后方面。这表明存在一种潜在的性别差异，即不同的分子机制在雄性和雌性中汇聚到相同的功能终点。
大脑中的一些性别差异可能是潜在差异，即雄性和雌性通过不同的潜在机制实现相同的功能终点。在此，我们报告了海马体中兴奋性突触分子调控方面的一种潜在性别差异。已知甾体17β-雌二醇能迅速增强两性的谷氨酸能突触传递。我们发现，这是通过增加两性突触前谷氨酸释放概率和增加突触后对谷氨酸的敏感性共同实现的，但不同的雌激素受体亚型是每种性别中增强作用各方面的基础。这些结果表明，针对特定雌激素受体亚型或其下游信号的治疗方法可能会对两性海马体中的突触传递产生不同影响。
