β-Estradiol unmasks metabotropic receptor-mediated metaplasticity of NMDA receptor transmission in the female rat dentate gyrus

Abstract

Loss of estrogen in women following menopause is associated with increased risk for cognitive decline, dementia and depression, all of which can be prevented by estradiol replacement. The dentate gyrus plays an important role in cognition, learning and memory. The gatekeeping function of the dentate gyrus to filter incoming activity into the hippocampus is modulated by estradiol in a frequency-dependent manner and involves activation of metabotropic glutamate receptors (mGluR). In the present study, we investigated whether estradiol (EB) modulates the metaplastic effect of inducing synaptic long-term potentiation (LTP) on subsequent propensity for expression of larger LTP in the dentate gyrus. At medial perforant path-dentate granule cell synapses in hippocampal slices of ovariectomized female rats, EB replacement was critical for an initial induction of LTP to enhance the magnitude of subsequent LTP elicited by a second high-frequency stimulation, metaplasticity, which was not present in slices from oil-treated control animals. EB enhanced expression of group I mGluRs, and the metaplastic effect of EB on LTP required activation of group I mGluRs that led to Src-family tyrosine kinase-mediated phosphorylation of NR2B subunits of N-methyl-D-aspartate receptors (NMDAR) that enhanced the magnitude of NMDAR-dependent LTP. Our data show that EB effects on LTP in the hippocampal dentate gyrus require activation of group I mGluRs, which in turn leads to functional metaplastic regulation of NR2B subunit-containing NMDARs, as opposed to direct effects of EB on NMDARs.

Estradiol rapidly modulates synaptic plasticity of hippocampal neurons: Involvement of kinase networks

“…1B1 and D). Coincubation of YM202074 (4 μM), an inhibitor of mGluR1 (Nebieridze et al, 2012), with E2 established LTP-induction by weak-TBS, with EPSP to 13074% (n¼8 slices) ( Fig. 1B2 and D).…”

Analysis of Kalirin-7 Knockout Mice Reveals Different Effects in Female Mice

“…There is widespread agreement that NR2B function increases in hippocampal CA1 pyramidal neurons after E2 treatment, but the mechanism is controversial, with reports of increased NR2B mRNA, protein, and protein phosphorylation (Xu et al, 2011;Nebieridze et al, 2012;Raval et al, 2012) in vivo, decreased NR2B phosphorylation in response to E2 using cultured cortical neurons (Liu et al, 2012), or enhanced recruitment of NR2B receptors to synapses but no change in protein or phosphorylation levels (Snyder et al, 2011). E2 treatment is known to increase extracellular signal-regulated kinase phosphorylation in hippocampus in an NMDA-dependent manner .…”

Gonadal status-dependent effects of in vivo β-estradiol administration to female rats on in vitro epileptiform activity induced by low [Mg2+]o in combined hippocampus-entorhinal cortex slices

“…Standard electrophysiological procedures were used (Nebieridze et al, 2012; Velíšek et al, 1999). At 24 hours following the last oil or EB injection, rats were decapitated under deep CO 2 anesthesia and brains removed.…”

“…At 24 hours following the last oil or EB injection, rats were decapitated under deep CO 2 anesthesia and brains removed. Combined hippocampal-entorhinal cortex slices were cut horizontally in ice-cold aCSF (composition in mM): KCl 5, MgSO 4 2, NaH 2 PO 4 1.2, CaCl 2 2, glucose 10, and NaHCO 3 26, gassed with 95% O 2 /5% CO 2 , pH=7.4, transferred to interface-type recording chamber to recover at 33-34 0 C in the aCSF for 1 hour (Nebieridze et al, 2012; Velíšek et al, 1999). Epileptiform activity was induced by perfusion with 0 Mg 2+ -containing aCSF (Velíšek et al, 1999).…”