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Neuropsychopharmacology DOI:10.1038/npp.2011.24

AKT kinase activity is required for lithium to modulate mood-related behaviors in mice.

Publication TypeJournal Article
Year of Publication2011
AuthorsPan, JQ, Lewis, MC, Ketterman, JK, Clore, EL, Riley, M, Richards, KR, Berry-Scott, E, Liu, X, Wagner, FF, Holson, EB, Neve, RL, Biechele, TL, Moon, RT, Scolnick, EM, Petryshen, TL, Haggarty, SJ
Date Published2011 Jun
KeywordsAmphetamine, Analysis of Variance, Animals, Antimanic Agents, Cell Line, Transformed, Corpus Striatum, Disease Models, Animal, Drug Administration Routes, Drug Administration Schedule, Drug Interactions, Enzyme Inhibitors, Gene Expression Regulation, Enzymologic, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Hippocampus, Humans, Lithium Chloride, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mood Disorders, Proto-Oncogene Proteins c-akt, Signal Transduction, Transfection

Bipolar disorder (BP) is a debilitating psychiatric disorder, affecting ∼2% of the worldwide population, for which the etiological basis, pathogenesis, and neurocircuitry remain poorly understood. Individuals with BP suffer from recurrent episodes of mania and depression, which are commonly treated with the mood stabilizer lithium. However, nearly half of BP patients do not respond adequately to lithium therapy and the clinically relevant mechanisms of lithium for mood stabilization remain elusive. Here, we modeled lithium responsiveness using cellular assays of glycogen synthase kinase 3 (GSK-3) signaling and mood-related behavioral assays in inbred strains of mice that differ in their response to lithium. We found that activating AKT through phosphosrylation of a key regulatory site (Thr308) was associated with lithium response-activation of signaling pathways downstream of GSK-3 in cells and attenuation of mood-related behaviors in mice-and this response was attenuated by selective and direct inhibition of AKT kinase activity. Conversely, the expression of constitutively active AKT1 in both the cellular and behavioral assays conferred lithium sensitivity. In contrast, selective and direct GSK-3 inhibition by the ATP-competitive inhibitor CHIR99021 bypassed the requirement for AKT activation and modulated behavior in both lithium-responsive and non-responsive mouse strains. These results distinguish the mechanism of action of lithium from direct GSK-3 inhibition both in vivo and in vitro, and highlight the therapeutic potential for selective GSK-3 inhibitors in BP treatment.


Alternate JournalNeuropsychopharmacology
PubMed ID21389981
PubMed Central IDPMC3096809
Grant ListMH087442-01 / MH / NIMH NIH HHS / United States
UL1RR024924 / RR / NCRR NIH HHS / United States
R21 MH087896 / MH / NIMH NIH HHS / United States
RL1HG004671 / HG / NHGRI NIH HHS / United States
RL1CA133834 / CA / NCI NIH HHS / United States
RL1GM084437 / GM / NIGMS NIH HHS / United States
R03 MH087442 / MH / NIMH NIH HHS / United States
UL1 RR024924 / RR / NCRR NIH HHS / United States
RL1 GM084437 / GM / NIGMS NIH HHS / United States
RL1 HG004671 / HG / NHGRI NIH HHS / United States
R21 MH087896-01 / MH / NIMH NIH HHS / United States
RL1 CA133834 / CA / NCI NIH HHS / United States