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...
A chemical form of synaptic potentiation was produced with a brief bath application of NMDA to rat hippocampal slices. Two methods were used to assess changes in membrane-bound AMPA receptors. Traditional subcellular fractionation was used to isolate synaptic membranes; alternatively, membrane receptors were cross-linked with the membrane-impermeable reagent bis(sulfosuccinimidyl) suberate, and levels of nonmembrane receptors were determined. In both cases, Western blots were used to determine the content of receptor subunits in various subcellular fractions. NMDA-induced potentiation was associated with increased levels of glutamate receptor 1 (GluR1) and GluR2/3 subunits of AMPA receptors in synaptic membrane preparations, whereas no change was observed in whole homogenates. Both KN-62, an inhibitor of calcium/calmodulin kinase, and calpain inhibitor III, a calpain inhibitor, inhibited NMDA-induced potentiation and changes in GluR1 and GluR2/3 subunits of AMPA receptors. Brefeldin A (BFA) inhibits protein trafficking between the Golgi apparatus and cell membranes. Pretreatment of hippocampal slices with BFA significantly decreased NMDA-induced potentiation and completely prevented an NMDA-induced increase in GluR1 levels in membrane fractions. Thus, the levels of GluR1 and GluR2/3 subunits of AMPA receptors are rapidly upregulated in synaptic membranes under conditions associated with potentiation of synaptic responses, and this upregulation requires a functional secretory pathway.
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