Estrogen replacement therapy in women is associated with improvement of cognitive deficits and reduced incidence of Alzheimer's disease. The present study indicates that estrogen is neuroprotective against N-methyl-D-aspartate (NMDA)-and kainate-mediated neurotoxicity, an effect mediated by tyrosine kinase͞ mitogen-activated protein kinase (MAPK) pathways. Estrogen also stimulates tyrosine phosphorylation of NMDA receptors via an src tyrosine kinase͞MAPK pathway. Finally, estrogen-mediated enhancement of long-term potentiation in hippocampal slices is mediated by activation of an src tyrosine kinase pathway. Thus, estrogen, by activating an src tyrosine kinase and the extracellular signal-related protein kinase͞MAPK signaling pathway, both enhances NMDA receptor function and long-term potentiation and retains neuroprotective properties against excitotoxicity. These findings warrant further evaluation of the usefulness of estrogenic compounds for the treatment of Alzheimer's disease and other neurodegenerative diseases. E strogen replacement therapy in postmenopausal women decreases the probability of developing Alzheimer's disease and slows the progress of the disease (1). In addition, estrogen replacement therapy improves cognitive performance in women with Alzheimer's disease (2-4). These effects of estrogen suggest that estrogen acts both as a cognitive enhancer and as a neuroprotective agent. Although the mechanisms underlying these effects remain unknown, estrogen has been shown to increase basal synaptic responses and the magnitude of longterm potentiation (LTP) in acute hippocampal slices (5-7). In addition, estrogen increased both ␣-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) and N-methyl-D-aspart ate (NMDA) receptor-mediated responses in hippocampal neurons (7-10). Such effects could account for the estrogen-mediated cognitive improvement in humans, because LTP is widely considered to represent a cellular model of learning and memory (11). Recent studies have also shown that estrogen is neuroprotective against excitotoxicity in primary neuronal cultures (12, 13). Estrogen-mediated neuroprotection involved the tyrosine kinase͞mitogen-activated protein kinase (MAPK) signal transduction cascade, because estrogen rapidly activated tyrosine kinase and MAPK activity (14, 15) and because the neuroprotective effect of estrogen against glutamate toxicity was blocked by inhibitors of tyrosine kinases and MAPK (16). The MAPK pathway is thought to play an important role in the action of neurotrophins and in synaptic plasticity (17, 18), and its activation could lead to increased expression of antiapoptotic genes. A vast literature indicates that tyrosine kinase directly phosphorylates some NMDA receptor subunits, thereby enhancing NMDA receptor function (19)(20)(21)(22)(23). In addition, fyn knockout mice have LTP impairment, suggesting that the tyrosine kinase pathway could be involved in LTP (24). In the present study, we used acute and cultured hippocampal slices to study the role of tyrosine kinase͞...

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...

Estrogen replacement therapy in women is associated with improvement of cognitive deficits and reduced incidence of Alzheimer's disease. The present study indicates that estrogen is neuroprotective against N-methyl-D-aspartate (NMDA)-and kainate-mediated neurotoxicity, an effect mediated by tyrosine kinase͞ mitogen-activated protein kinase (MAPK) pathways. Estrogen also stimulates tyrosine phosphorylation of NMDA receptors via an src tyrosine kinase͞MAPK pathway. Finally, estrogen-mediated enhancement of long-term potentiation in hippocampal slices is mediated by activation of an src tyrosine kinase pathway. Thus, estrogen, by activating an src tyrosine kinase and the extracellular signal-related protein kinase͞MAPK signaling pathway, both enhances NMDA receptor function and long-term potentiation and retains neuroprotective properties against excitotoxicity. These findings warrant further evaluation of the usefulness of estrogenic compounds for the treatment of Alzheimer's disease and other neurodegenerative diseases. E strogen replacement therapy in postmenopausal women decreases the probability of developing Alzheimer's disease and slows the progress of the disease (1). In addition, estrogen replacement therapy improves cognitive performance in women with Alzheimer's disease (2-4). These effects of estrogen suggest that estrogen acts both as a cognitive enhancer and as a neuroprotective agent. Although the mechanisms underlying these effects remain unknown, estrogen has been shown to increase basal synaptic responses and the magnitude of longterm potentiation (LTP) in acute hippocampal slices (5-7). In addition, estrogen increased both ␣-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) and N-methyl-D-aspart ate (NMDA) receptor-mediated responses in hippocampal neurons (7-10). Such effects could account for the estrogen-mediated cognitive improvement in humans, because LTP is widely considered to represent a cellular model of learning and memory (11). Recent studies have also shown that estrogen is neuroprotective against excitotoxicity in primary neuronal cultures (12, 13). Estrogen-mediated neuroprotection involved the tyrosine kinase͞mitogen-activated protein kinase (MAPK) signal transduction cascade, because estrogen rapidly activated tyrosine kinase and MAPK activity (14, 15) and because the neuroprotective effect of estrogen against glutamate toxicity was blocked by inhibitors of tyrosine kinases and MAPK (16). The MAPK pathway is thought to play an important role in the action of neurotrophins and in synaptic plasticity (17, 18), and its activation could lead to increased expression of antiapoptotic genes. A vast literature indicates that tyrosine kinase directly phosphorylates some NMDA receptor subunits, thereby enhancing NMDA receptor function (19)(20)(21)(22)(23). In addition, fyn knockout mice have LTP impairment, suggesting that the tyrosine kinase pathway could be involved in LTP (24). In the present study, we used acute and cultured hippocampal slices to study the role of tyrosine kinase͞...