AKT Kinase Activity Is Required for Lithium to Modulate Mood-Related Behaviors in Mice

Abstract

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.

Fine-Tuning of the RIG-I-Like Receptor/Interferon Regulatory Factor 3-Dependent Antiviral Innate Immune Response by the Glycogen Synthase Kinase 3/β-Catenin Pathway

“…As pharmacological inhibitors are prone to off-target effects, we used the GSK-3 inhibitors at low concentrations (2 to 5 M). Other studies have used CHIR (57)(58)(59)(60)(61), BIO (62,63), and BIO-ac (38,64) at concentrations as high as 10 to 20 M. Moreover, reconstitution of DKO ES cells with kinase-dead forms of GSK-3␣ and GSK-3␤ showed decreased antiviral mRNA expression compared to that obtained by reconstitution with WT forms. Although we do not completely rule out a kinase-independent function for GSK-3 in innate immunity, our data obtained with DKO ES cells and GSK-3 inhibitors (Fig.…”

Antidepressant Activity of Astilbin: Involvement of Monoaminergic Neurotransmitters and BDNF Signal Pathway

“…8,42,43) Therefore, we next examined whether AKT pathway participated in the action of antidepressant of AST. As shown in Figs.…”

Lithium: the pharmacodynamic actions of the amazing ion

“…Lithium is able to activate Akt by disrupting the formation of a protein kinase B (Akt), beta-arrestin 2(βArr2) and protein phosphatase 2A (Akt;βArr2;PP2A) comprised signalling complex, triggered by activation of the dopaminelithium's pharmacodynamic actions. Evidence of its therapeutic relevance is emerging from animal studies, which link GSK3 and manic-or depressive-like behaviours [Beaulieu et al 2004;Gould et al 2004;Kaidanovich-Beilin et al 2004;O'Brien et al 2004, Prickaerts et al 2006Polter et al 2010], potentially due to lithium-induced Akt activation [Pan et al 2011]. Furthermore, abnormal GSK3 activity appears to occur in humans with depression [Karege et al 2007;Inkster et al 2009] and bipolar disorder [Polter et al 2010].…”