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The Journal of Neuroscience, May 1, 2003, 23(9):3679
Phosphatidylinositol 3-Kinase Regulates the Induction of Long-Term Potentiation through Extracellular Signal-Related Kinase-Independent Mechanisms
Patricio Opazo1, Ayako M. Watabe1, Seth G. N. Grant2, and Thomas J. O'Dell1 1 Department of Physiology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California 90095, and 2 Department of Neuroscience, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom
Inhibitors of both phosphatidylinositol-3-kinase (PI3-kinase) and MAPK/ERK (mitogen-activate protein kinase/extracellular signal-related kinase) activation inhibit NMDA receptor-dependent long-term potentiation (LTP). PI3-kinase inhibitors also block activation of ERK by NMDA receptor stimulation, suggesting that PI3-kinase inhibitors block LTP because PI3-kinase is an essential upstream regulator of ERK activation. To examine this hypothesis, we investigated the effects of PI3-kinase inhibitors on ERK activation and LTP induction in the CA1 region of mouse hippocampal slices. Consistent with the notion that ERK activation by NMDA receptor stimulation is PI3-kinase dependent, the PI3-kinase inhibitor wortmannin partially inhibited ERK2 activation induced by bath application of NMDA and strongly suppressed ERK2 activation by high-frequency synaptic stimulation. PI3-kinase and MEK (MAP kinase kinase) inhibitors had very different effects on LTP, however. Both types of inhibitors suppressed LTP induced by theta-frequency trains of synaptic stimulation, but only PI3-kinase inhibitors suppressed the induction of LTP by high-frequency stimulation or low-frequency stimulation paired with postsynaptic depolarization. Concentrations of PI3-kinase inhibitors that inhibited LTP when present during high-frequency stimulation had no effect on potentiated synapses when applied after high-frequency stimulation, suggesting that PI3-kinase is specifically involved in the induction of LTP. Finally, we found that LTP induced by theta-frequency stimulation was MEK inhibitor insensitive but still PI3-kinase dependent in hippocampal slices from PSD-95 (postsynaptic density-95) mutant mice. Together, our results indicate that the role of PI3-kinase in LTP is not limited to its role as an upstream regulator of MAPK signaling but also includes signaling through ERK-independent pathways that regulate LTP induction.
Key words: long-term potentiation; hippocampus; phosphatidylinositol 3-kinase; extracellular signal-related kinase II; NMDA receptor;
-adrenergic receptor
Copyright © 2003 Society for Neuroscience 0270-6474/03/2393679-10$05.00/0
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