Bidirectional modulatory effect of 17β-estradiol on NMDA receptors via ERα and ERβ in the dentate gyrus of juvenile male rats.

The neurosteroid 17β-estradiol (E2) is synthesized by aromatase in both male and female hippocampi and is known to modulate hippocampal synaptic functions. However, as some contradictory findings regarding the modulatory effects of E2 have been reported in the literature, its physiological role and mechanism of action in the hippocampus remain controversial. Our recent study showed that a low E2 dose (1 nM) increased the amplitude of NMDA receptor-mediated EPSCs (NMDAR-EPSCs) and lowered the threshold for the induction of NMDA receptor-dependent long-term potentiation (NMDAR-LTP), while a high E2 dose (7 nM) exerted opposite effects in the dentate gyrus of juvenile male rat hippocampal slices. The present study is a follow-up that explores the underlying mechanism of this bidirectional effect of E2. We found that the ERα agonist PPT reproduced the actions of the low E2 dose on NMDAR-EPSCs and NMDAR-LTP, while the ERβ agonist DPN reproduced the actions of the high E2 dose. Moreover, PPT, but not DPN, restored the decrease in NMDAR-EPSCs induced by the aromatase inhibitor letrozole, suggesting that E2 synthesized constitutively in the hippocampus enhances NMDA receptor function via ERα. The PPT-induced enhancement in NMDAR-EPSCs was mediated by Src family kinase, but was not caused by NR2B modulation. These findings demonstrate that E2 exerts condition-dependent bidirectional effects on NMDA receptor-mediated transmission and, thus, synaptic plasticity via ERα and ERβ in the dentate gyrus of juvenile male rats.