Cyclic changes in estradiol regulate synaptic plasticity through the MAP kinase pathway

Abstract

Hippocampal synaptic structure and function exhibit marked variations during the estrus cycle of female rats. Estradiol activates the mitogen-activated protein (MAP) kinase pathway in numerous cell types, and MAP kinase has been shown to play a critical role in the mechanisms underlying synaptic plasticity. Here, we report that endogenous estrogen produces a tonic phosphorylation͞activa-tion of extracellular signal-regulated kinase 2 (ERK2)͞MAP kinase throughout the female rat brain and an increase in tyrosine phosphorylation of NR2 subunits of N-methyl-D-aspartate (NMDA) receptors. Moreover, cyclic changes in estrogen levels during the estrus cycle of female rats are associated with corresponding changes in the levels of activation of ERK2, the state of tyrosine phosphorylation of NR2 subunits of NMDA receptors, and the magnitude of long-term potentiation in hippocampus. Thus, cyclic changes in female sexual hormones result in marked variations in the state of activation of a major cellular signaling pathway critical for learning and memory and in a cellular model of learning and memory.E strogens have profound effects on hippocampal structure and physiology (1-4) and on hippocampal-dependent learning and memory (5, 6). In particular, estrogens have been shown to increase the density of dendritic spines on CA1 pyramidal neurons (7). In hippocampal slices, 17␤-estradiol increases electrophysiological responses elicited by activation of both ␣-amino-3-hydroxy-5-methylisoxazole propionic acid and N-methyl-Daspartate (NMDA) receptors and the magnitude of long-term potentiation (LTP) in field CA1 (8, 9). At the cellular level, numerous laboratories have shown that, in addition to direct genomic effects, 17␤-estradiol activates the extracellular regulated kinase͞mitogen-activated protein (ERK͞MAP) kinase pathway (10-12), an effect associated with the neurotrophic͞ neuroprotective actions of estrogen (13,14). We recently reported that estrogen-mediated activation of the ERK͞MAP kinase pathway in hippocampus was involved in the rapid effects of estrogen on NMDA receptors and LTP through tyrosine phosphorylation of NR2 subunits of NMDA receptors (15).The ERK͞MAP kinase pathway is a central cellular signaling pathway linking numerous extracellular signals to membrane receptors, transcription factors, and gene regulation (16) and is critically involved in synaptic plasticity, learning, and memory (17)(18)(19)(20). Pharmacological manipulations directed at blocking this pathway have consistently produced impairment in synaptic plasticity, learning, and memory, and this pathway is activated with LTP-inducing tetanus or in different learning paradigms. The present study analyzed whether endogenous estrogen regulates the state of activation of the ERK͞MAP kinase pathway and whether cyclic variations in estrogen levels during the female estrus cycle suffice to modify this pathway in the brain. Moreover, we determined the state of tyrosine phosphorylation of NMDA-receptor subunits, as well as the magnitude of LTP in field CA1 o...

DREAM/calsenilin/KChIP3 modulates strategy selection and estradiol-dependent learning and memory

“…This result is consistent with previous data that showed LTP is enhanced when female rats are in proestrus, a point in the estrous cycle where endogenous estradiol levels are highest (Warren et al 1995). A similar increase of LTP induction is observed in slices taken from the cycling rat at proestrus (Bi et al 2001). This effect appears to be mediated by estradiol, as LTP is enhanced in ovariectomized rats treated acutely with estradiol (Cordoba Montoya and Carrer 1997).…”

Membrane-initiated estrogen signaling in hypothalamic neurons

“…Such signals that are initiated by E2 at the plasma membrane can trigger intracellular signaling events that result in gene transcription. New gene transcription can result from E2 activation of multiple intracellular kinase cascades including MAPK, phosphoinositide 3-kinase (PI3K), cAMP-protein kinase (PKA) and protein kinase C (PKC) pathways (Watters et al, 1997, Bi et al, 2001, Cato et al, 2002, Yang et al, 2003, Deisseroth et al, 2003. These events are often termed rapid signaling cascades because they are initiated at the plasma membrane or in the cytoplasm and occur much faster than ERE-driven events (Bryant et al, 2005, Björnström andSjöberg, 2005).…”

Hippocampal Synapses Depend on Hippocampal Estrogen Synthesis

“…In addition, estrogen effects are presumed to be mediated by putative, as yet not identified, membrane-bound receptors (Moss et al, 1997;Revelli, 1998;Razandi et al, 1999;ToranAllerand, 2002). This would imply that estrogens share common signal transduction pathways with other signal molecules (e.g., neurotrophic factors) (Linford et al, 2000;Balthazart et al, 2001;Bi et al, 2001;Björnström and Sjöberg, 2002;Shingo and Kito, 2002). In fact, such a cross talk between estrogens and neurotrophins has been documented (for review, see Toran-Allerand et al, 1999;Toran-Allerand, 2000).…”