LTP varies across the estrous cycle: enhanced synaptic plasticity in proestrus rats

Warren, Stacey G.; Humphreys, Aaron G.; Juraska, Janice M.; Greenough, William T.

doi:10.1016/0006-8993(95)01059-9

Cited by 407 publications

(282 citation statements)

References 24 publications

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“…This finding fits well with our previous results showing that estrogen, by activating the MAP kinase pathway and by increasing the state of tyrosine phosphorylation of NR2 subunits of NMDA receptors, produced an increase in the magnitude of LTP in hippocampal slices (15). It is also consistent with reports indicating facilitation of LTP induction by estrogen in ovariectomized female rats (24), increased LTP in the afternoon of proestrus of female rats (25), and increased LTP magnitude in proestrus as compared with diestrus in CA1 of adult female rats (26). Therefore, we propose that circulating levels of estrogen regulate the phosphorylation͞ activation state of ERK2.…”

Section: Discussionsupporting

confidence: 93%

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

Foy

Vouimba³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

182

124

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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...

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Section: Discussionsupporting

confidence: 93%

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

Foy

Vouimba³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

182

124

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“…The effects of estradiol on spine density and LTP were frequently shown by either using ovariectomized animals, which had been treated systemically with estradiol (Gould et al, 1990;Warren et al, 1995;Có rdoba Montoya and Carrer, 1997;Smith and McMahon, 2005;Kramár et al, 2009), by applying estradiol to acute slices of mostly male rats (Foy et al, 1999;Ito et al, 1999;Mukai et al, 2007;Kramár et al, 2009), or by using mixed hippocampal slice cultures from neonatal males and females (Murphy and Segal, 1996;Kretz et al, 2004;Mendez et al, 2011). Thus, the vast majority of studies do not consider the potential differences between males and females.…”

Section: Introductionmentioning

confidence: 99%

Aromatase Inhibition Abolishes LTP Generation in Female But Not in Male Mice

Vierk

Glassmeier²,

Zhou³

et al. 2012

Journal of Neuroscience

152

137

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Inhibitors of aromatase, the final enzyme of estradiol synthesis, are suspected of inducing memory deficits in women. In previous experiments, we found hippocampal spine synapse loss in female mice that had been treated with letrozole, a potent aromatase inhibitor. In this study, we therefore focused on the effects of letrozole on long-term potentiation (LTP), which is an electrophysiological parameter of memory and is known to induce spines, and on phosphorylation of cofilin, which stabilizes the spine cytoskeleton and is required for LTP in mice. In acute slices of letrozole-treated female mice with reduced estradiol serum concentrations, impairment of LTP started as early as after 6 h of treatment and progressed further, together with dephosphorylation of cofilin in the same slices. Theta-burst stimulation failed to induce LTP after 1 week of treatment. Impairment of LTP was followed by spine and spine synapse loss. The effects were confirmed in vitro by using hippocampal slice cultures of female mice. The sequence of effects in response to letrozole were similar in ovariectomized female and male mice, with, however, differences as to the degree of downregulation. Our data strongly suggest that impairment of LTP, followed by loss of mushroom spines and spine synapses in females, may have implications for memory deficits in women treated with letrozole.

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“…The gonadal hormone estradiol (E2) has beneficial effects on the formation of hippocampus-dependent memory (Farr et al, 1995;O'Neal et al, 1996;Gibbs et al, 1998;Shors et al, 1998;Leuner et al, 2004;Rhodes and Frye, 2004). During the estrous cycle, pyramidal cells in the hippocampus are subject to major changes including morphological changes (Woolley and McEwen, 1993;Adams et al, 2001) and modifications in synaptic efficacy (Warren et al, 1995;Cordoba Montoya and Carrer, 1997;Good et al, 1999;Vouimba et al, 2000;Mukai et al, 2007). Yet, it is not known whether E2 also affects cerebellar memory formation, despite the prominent presence of estrogen receptors (ERs) in the cerebellum (Shughrue et al, 1997;Price and Handa, 2000).…”

Section: Introductionmentioning

confidence: 99%

Estradiol Improves Cerebellar Memory Formation by Activating Estrogen Receptor β

Andreescu¹,

Milojkovic²,

Haasdijk³

et al. 2007

J. Neurosci.

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Learning motor skills is critical for motor abilities such as driving a car or playing piano. The speed at which we learn those skills is subject to many factors. Yet, it is not known to what extent gonadal hormones can affect the achievement of accurate movements in time and space. Here we demonstrate via different lines of evidence that estradiol promotes plasticity in the cerebellar cortex underlying motor learning. First, we show that estradiol enhances induction of long-term potentiation at the parallel fiber to Purkinje cell synapse, whereas it does not affect long-term depression; second, we show that estradiol activation of estrogen receptor ␤ receptors in Purkinje cells significantly improves gain-decrease adaptation of the vestibulo-ocular reflex, whereas it does not affect general eye movement performance; and third, we show that estradiol increases the density of parallel fiber to Purkinje cell synapses, whereas it does not affect the density of climbing fiber synapses. We conclude that estradiol can improve motor skills by potentiating cerebellar plasticity and synapse formation. These processes may be advantageous during periods of high estradiol levels of the estrous cycle or pregnancy.

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LTP varies across the estrous cycle: enhanced synaptic plasticity in proestrus rats

Cited by 407 publications

References 24 publications

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

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

Aromatase Inhibition Abolishes LTP Generation in Female But Not in Male Mice

Estradiol Improves Cerebellar Memory Formation by Activating Estrogen Receptor β

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