Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression.
Hippocampal long-term depression (LTD) is a long-lasting decrease in synaptic strength that is most commonly studied at glutamatergic inputs to pyramidal cells in hippocampal area CA1. Activation of G-protein-coupled group I (including types 1 and 5) metabotropic glutamate receptors (mGluRs) by the pharmacological agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) elicits LTD in area CA1 of the hippocampus. Recent reports have shown that de novo protein synthesis is necessary for DHPG-induced LTD. However, relatively little is known about the signaling pathways that couple mGluRs to translation initiation. In this study, we investigated whether the activation of the phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway, which has been shown to regulate translation initiation, is necessary for mGluR-LTD induced by DHPG. We found that brief incubations of mouse hippocampal slices with DHPG resulted in increased phosphorylation of Akt and mTOR in hippocampal area CA1. Two structurally unrelated PI3K inhibitors, LY294002 and wortmannin, blocked the DHPG-induced increases in phosphorylation of Akt and mTOR. Biochemical fractionation studies showed that the DHPG-induced increase in the phosphorylation of Akt and mTOR could be detected in synaptoneurosome preparations, and immunohistochemical analysis revealed that similar increases could be detected in both stratum pyramidale and stratum radiatum in area CA1. Finally, we observed that both PI3K inhibitors and rapamycin, an mTOR inhibitor, prevented mGluR-LTD induced by DHPG. Together, our findings indicate that activation of the PI3K-Akt-mTOR signaling cascade is required for mGluR-LTD and suggest that this pathway may couple group I mGluRs to translation initiation in hippocampal area CA1.
Hou
Lingfei
L
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Klann
Eric
E
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology*; D012118:Resorcinols / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077191:Wortmannin
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000730:Androstadienes; D001565:Benzoates; D002867:Chromones; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D005998:Glycine; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D016559:Tacrolimus; D000077191:Wortmannin; C104077:metabotropic glutamate receptor type 1; C079694:alpha-methyl-4-carboxyphenylglycine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C079215:3,5-dihydroxyphenylglycine; C121465:6-methyl-2-(phenylethynyl)pyridine; C058028:immunomycin; C546843:mTOR protein, mouse