17β-Estradiol Acutely Potentiates Glutamatergic Synaptic Transmission in the Hippocampus through Distinct Mechanisms in Males and Females.

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. SIGNIFICANCE STATEMENT: 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.