title: GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine.
abstract: A single dose of the short-acting NMDA antagonist ketamine produces rapid and prolonged antidepressant effects in treatment-resistant patients with major depressive disorder (MDD), which are thought to occur via restoration of synaptic connectivity. However, acute dissociative side effects and eventual fading of antidepressant effects limit widespread clinical use of ketamine. Recent studies in medial prefrontal cortex (mPFC) show that the synaptogenic and antidepressant-like effects of a single standard dose of ketamine in rodents are dependent upon activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway together with inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3), which relieves its inhibitory in influence on mTOR. Here, we found that the synaptogenic and antidepressant-like effects of a single otherwise subthreshold dose of ketamine were potentiated when given together with a single dose of lithium chloride (a nonselective GSK-3 inhibitor) or a preferential GSK-3β inhibitor; these effects included rapid activation of the mTORC1 signaling pathway, increased inhibitory phosphorylation of GSK-3β, increased synaptic spine density/diameter, increased excitatory postsynaptic currents in mPFC layer V pyramidal neurons, and antidepressant responses that persist for up to 1 week in the forced-swim test model of depression. The results demonstrate that low, subthreshold doses of ketamine combined with lithium or a selective GSK-3 inhibitor are equivalent to higher doses of ketamine, indicating the pivotal role of the GSK-3 pathway in modulating the synaptogenic and antidepressant responses to ketamine. The possible mitigation by GSK-3 inhibitors of the eventual fading of ketamine's antidepressant effects remains to be explored.
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Rong-Jian
authors.initials: RJ
authors.lastname: Liu
authors.forename: Manabu
authors.initials: M
authors.lastname: Fuchikami
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dwyer
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Lepack
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
authors.forename: George K
authors.initials: GK
authors.lastname: Aghajanian
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D049229:Dendritic Spines / Q000187:drug effects / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046353:Immobility Response, Tonic / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D007211:Indoles; D008301:Maleimides; D046912:Multiprotein Complexes; C417521:SB 216763; D007649:Ketamine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride