Phosphatidylinositol 3-kinase regulates the induction of long-term potentiation through extracellular signal-related kinase-independent mechanisms.
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.
Department of Physiology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, California 90095, USA.
Patricio
P
Opazo
Ayako M
AM
Watabe
Seth G N
SG
Grant
Thomas J
TJ
O'Dell
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D000076122:Disks Large Homolog 4 Protein; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D051528:Guanylate Kinases; D006624:Hippocampus / Q000201:enzymology / Q000502:physiology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000077191:Wortmannin
D000730:Androstadienes; D002070:Butadienes; D002867:Chromones; D000076122:Disks Large Homolog 4 Protein; D004791:Enzyme Inhibitors; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D016202:N-Methylaspartate; D009419:Nerve Tissue Proteins; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D000077191:Wortmannin; C501447:Dlg4 protein, mouse; C113580:U 0126; C033652:postsynaptic density proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one