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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.

SUBMITTER: Pan JQ

PROVIDER: S-EPMC3096809 | biostudies-other | 2011 Jun

REPOSITORIES: biostudies-other

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

Pan Jen Q JQ Lewis Michael C MC Ketterman Josh K JK Clore Elizabeth L EL Riley Misha M Richards Keenan R KR Berry-Scott Erin E Liu Xiulin X Wagner Florence F FF Holson Edward B EB Neve Rachael L RL Biechele Travis L TL Moon Randall T RT Scolnick Edward M EM Petryshen Tracey L TL Haggarty Stephen J SJ

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20110309 7

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 elusi ...[more]

PMID: 21389981

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Project description:Major depressive disorder (MDD) and bipolar disorder (BD) are the most prevalent mood disorders and cause considerable burden worldwide. Compelling evidence suggests a pronounced overlap between these two diseases in clinical symptoms, treatment strategies, and genetic etiology. Here we use a BD GWAS (1822 cases and 4650 controls) and a MDD GWAS (5303 cases and 5337 controls) of Han Chinese origin to investigate their shared genetic basis, followed by exploration of the underlying mechanisms. The lead SNP in the Han Chinese meta-analysis, rs126277 at the 1q32.2 locus, also exhibited nominal associations with mood disorders as well as several sub-clinical phenotypes (e.g., mania) related to mood disorders (UK biobank samples) in European populations. Bulk tissue and single-cell eQTL studies suggest that the risk G-allele of rs126277 predicted lower SYT14 mRNA expression in human brain tissues and cells, indicating possible involvement of this gene in mood disorders. We generated mice lacking Syt14 (Syt14–/–) and mice with insufficient expression of Syt14 in the hippocampus (Syt14-KD). We found that depletion of Syt14 resulted in mania-like behaviors including hyperactivity and anti-depressive behaviors, resembling aspects of mood disorders. We also confirmed that deficiency of this gene in the hippocampus was sufficient to induce hyperactivity in the mice. RNA-sequencing analyses of the hippocampus of Syt14–/– mice revealed significant upregulation of Per1 as well as downregulation of Slc7a11 and Ptprb. Ultrastructural analyses showed significant alteration of the number of vesicles within 50 nm to the active zone and the width of synaptic cleft in the ventral hippocampus of Syt14–/– mice compared with control mice. And Syt14–/– mice exhibit aberrant glutamate signaling patterns in the hippocampus. Overall, we have identified a novel mood disorder risk gene SYT14, and confirmed its impact on mania-like behaviors and essential roles in synaptic function. While the current study provides clues for the pathological mechanisms of mood disorders, further investigations elucidating the detailed mechanisms by which SYT14 regulates mood disorders-related traits are needed.

Dataset Information

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

Publications

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

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