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PMID: 12736339 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Phosphatidylinositol 3-kinase regulates the induction of long-term potentiation through extracellular signal-related kinase-independent mechanisms.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 23 ·No. 9 ·2003-05-01 ·Pages 3679-88

Opazo P, Watabe AM, Grant SG, O'Dell TJ

Abstract

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.

MeSH Terms
Androstadienes/pharmacology Animals Butadienes/pharmacology Chromones/pharmacology Disks Large Homolog 4 Protein Electric Stimulation Enzyme Inhibitors/pharmacology Excitatory Postsynaptic Potentials/drug effects,physiology Guanylate Kinases Hippocampus/enzymology,physiology In Vitro Techniques Intracellular Signaling Peptides and Proteins Long-Term Potentiation/drug effects,physiology Membrane Proteins Mice Mice, Inbred C57BL Mitogen-Activated Protein Kinases/antagonists & inhibitors,metabolism Morpholines/pharmacology N-Methylaspartate/pharmacology Nerve Tissue Proteins/genetics,metabolism Nitriles/pharmacology Patch-Clamp Techniques Phosphatidylinositol 3-Kinases/metabolism Phosphoinositide-3 Kinase Inhibitors Receptors, N-Methyl-D-Aspartate/metabolism Signal Transduction/physiology Wortmannin
Chemicals
Androstadienes Butadienes Chromones Disks Large Homolog 4 Protein Dlg4 protein, mouse Enzyme Inhibitors Intracellular Signaling Peptides and Proteins Membrane Proteins Morpholines Nerve Tissue Proteins Nitriles Phosphoinositide-3 Kinase Inhibitors Receptors, N-Methyl-D-Aspartate U 0126 postsynaptic density proteins 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one N-Methylaspartate Mitogen-Activated Protein Kinases Guanylate Kinases Wortmannin
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Opazo Patricio
Department of Physiology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California 90095, USA.
Watabe Ayako M
Grant Seth G N
O'Dell Thomas J
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
2003-05-01
Pages
3679-88
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6742185
Subset
IM
Grants
Wellcome Trust · United Kingdom
External Links
PubMed source PMC Full Text View journal details
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