title: Synaptic stimulation of mTOR is mediated by Wnt signaling and regulation of glycogen synthetase kinase-3.
abstract: The persistent or "late" phase of long-term potentiation (L-LTP), which requires protein synthesis, can be induced by relatively intense synaptic activity. The ability of such strong synaptic protocols to engage the translational machinery and produce plasticity-related proteins, while weaker protocols activate only posttranslational processes and transient potentiation (early LTP; E-LTP), is not understood. Among the major translation control pathways in neurons, the stimulation of mammalian target of rapamycin (mTOR) is a key event in the induction of L-LTP. We report that mTOR is tonically suppressed in rat hippocampus under resting conditions, a consequence of the basal activity of glycogen synthetase kinase 3 (GSK3). This suppression could be overcome by weak synaptic stimulation in the presence of the β-adrenergic agonist isoproterenol, a combination that induced L-LTP, and activation of mTOR coincided with the Akt-mediated phosphorylation of GSK3. Surprisingly, while isoproterenol alone elevated Akt activity, it failed to increase GSK3 phosphorylation or mTOR signaling, showing that Akt was uncoupled from these effectors in the absence of synaptic stimulation. With the addition of weak stimulation, Akt signaled to GSK3 and mTOR, a gating effect that was mediated by voltage-dependent Ca(2+) channels and the Wnt pathway. mTOR could be stimulated by pharmacological inhibition, enabling weak HFS to induce L-LTP. These results establish GSK3 as an integrator of Akt and Wnt signals and suggest that overcoming GSK3-mediated suppression of mTOR is a key event in the induction of L-LTP by synaptic activity.
authors: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors: Tao
authors: T
authors: Ma
authors: Nikos
authors: N
authors: Tzavaras
authors: Panayiotis
authors: P
authors: Tsokas
authors: Emmanuel M
authors: EM
authors: Landau
authors: Robert D
authors: RD
authors: Blitzer
mesh_terms: D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D051153:Wnt Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3