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Estrogen Enhances Depolarization-Induced Glutamate Release through Activation of Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase in Cultured Hippocampal Neurons

Division of Protein Biosynthesis (D.Y., T.N., Y.N., S.S., T.M., N.A., C.N., H.H.), Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan; and Neuronics Research Group (D.Y., T.N., T.M., T.T.), and Cell Dynamics Research Group (S.S.), Special Division for Human Life Technology, National Institute of Advanced Industrial Science and Technology, Ikeda Osaka 563-8577, Japan

Address all correspondence and requests for reprints to: Tadahiro Numakawa, Ph.D., Neuronics Research Group, Special Division for Human Life Technology, National Institute of Advanced Industrial Science and Technology, 1-8-31, Midorigaoka, Ikeda, Osaka 563-8577, Japan. E-mail: t-numakawa{at}aist.go.jp.

Changes in synaptic efficacy are considered necessary for learning and memory. Recently, it has been suggested that estrogen controls synaptic function in the central nervous system. However, it is unclear how estrogen regulates synaptic function in central nervous system neurons. We found that estrogen potentiated presynaptic function in cultured hippocampal neurons. Chronic treatment with estradiol (1 or 10 nM) for 24 h significantly increased a high potassium-induced glutamate release. The estrogen-potentiated glutamate release required the activation of both phosphatidylinositol 3-kinase and MAPK.

The high potassium-evoked release with or without estradiol pretreatment was blocked by tetanus neurotoxin, which is an inhibitor of exocytosis. In addition, the reduction in intensity of FM1-43 fluorescence, which labeled presynaptic vesicles, was enhanced by estradiol, suggesting that estradiol potentiated the exocytotic mechanism. Furthermore, protein levels of synaptophysin, syntaxin, and synaptotagmin (synaptic proteins, respectively) were up-regulated by estradiol. We confirmed that the up-regulation of synaptophysin was blocked by the MAPK pathway inhibitor, U0126. These results suggested that estrogen enhanced presynaptic function through the up-regulated exocytotic system. In this study, we propose that estrogen reinforced excitatory synaptic transmission via potentiated-glutamate release from presynaptic sites.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ

Ligands:   17β-Estradiol  |  Progesterone

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