Regulation of glycogen synthase kinase-3 during bipolar mania treatment

Beijing Anding Hospital, Capital Medical University, 1720 Seventh Avenue South, Beijing, China.
Bipolar Disorders (Impact Factor: 4.97). 11/2010; 12(7):741-52. DOI: 10.1111/j.1399-5618.2010.00866.x
Source: PubMed


Bipolar disorder is a debilitating psychiatric illness presenting with recurrent mania and depression. The pathophysiology of bipolar disorder is poorly understood, and molecular targets in the treatment of bipolar disorder remain to be identified. Preclinical studies have suggested that glycogen synthase kinase-3 (GSK3) is a potential therapeutic target in bipolar disorder, but evidence of abnormal GSK3 in human bipolar disorder and its response to treatment is still lacking.
This study was conducted in acutely ill type I bipolar disorder subjects who were hospitalized for a manic episode. The protein level and the inhibitory serine phosphorylation of GSK3 in peripheral blood mononuclear cells of bipolar manic and healthy control subjects were compared, and the response of GSK3 to antimanic treatment was evaluated.
The levels of GSK3α and GSK3β in this group of bipolar manic subjects were higher than healthy controls. Symptom improvement during an eight-week antimanic treatment with lithium, valproate, and atypical antipsychotics was accompanied by a significant increase in the inhibitory serine phosphorylation of GSK3, but not the total level of GSK3, whereas concomitant electroconvulsive therapy treatment during a manic episode appeared to dampen the response of GSK3 to pharmacological treatment.
Results of this study suggest that GSK3 can be modified during the treatment of bipolar mania. This finding in human bipolar disorder is in agreement with preclinical data suggesting that inhibition of GSK3 by increasing serine phosphorylation is a response of GSK3 to psychotropics used in bipolar disorder, supporting the notion that GSK3 is a promising molecular target in the pharmacological treatment of bipolar disorder.

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    • "Selective dopamine transporter (DAT) inhibitors – i.e. GBR12909 – or DAT knockdown have been used to model long-lasting behavioural profiles in mice consistent with manic phenotypes in patients with BD, that however differ from those induced by amphetamine administration (Perry et al., 2009; Ralph-Williams et al., 2003; Young et al., 2010a, 2011) (Table 1). These observations may suggest that the dysregulation in dopamine homeostasis in patients with BD could mainly rely on impairments in dopamine reuptake mechanisms, rather than on altered presynaptic functions. "
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    ABSTRACT: Aberrant synaptic plasticity, originating from abnormalities in dopamine and/or glutamate transduction pathways, may contribute to the complex clinical manifestations of bipolar disorder (BD). Dopamine and glutamate systems cross-talk at multiple levels, such as at the postsynaptic density (PSD). The PSD is a structural and functional protein mesh implicated in dopamine and glutamate-mediated synaptic plasticity. Proteins at PSD have been demonstrated to be involved in mood disorders pathophysiology and to be modulated by antipsychotics and mood stabilizers. On the other side, post-receptor effectors such as protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3) and the extracellular signal-regulated kinase (Erk), which are implicated in both molecular abnormalities and treatment of BD, may interact with PSD proteins, and participate in the interplay of the dopamine-glutamate signalling pathway. In this review, we describe emerging evidence on the molecular cross-talk between dopamine and glutamate signalling in BD pathophysiology and pharmacological treatment, mainly focusing on dysfunctions in PSD molecules. We also aim to discuss future therapeutic strategies that could selectively target the PSD-mediated signalling cascade at the crossroads of dopamine-glutamate neurotransmission.
    Journal of Psychopharmacology 02/2014; 28(6). DOI:10.1177/0269881114523864 · 3.59 Impact Factor
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    • "—Lithium, an inorganic element administered as a salt for the treatment of BD, is a powerful inhibitor of GSK3β. Lithium can inhibit GSK3β directly via competition with magnesium and indirectly by increasing inhibitory serine-phosphorylation of GSK3 through Akt (Li et al., 2010b) (reviewed in Beaulieu and Gainetdinov, 2011; Polter et al., 2010) (Figure 3). Together, these GSK3 inhibitory mechanisms likely mediate the behavioral effects of lithium (Beaulieu et al., 2004) and it is thus possible that myelination is involved in its mechanism of action (Azim and Butt, 2011) (reviewed in Bartzokis, 2011b) (Figure 3). "
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    ABSTRACT: Current psychiatric diagnostic schema segregate symptom clusters into discrete entities, however, large proportions of patients suffer from comorbid conditions that fit neither diagnostic nor therapeutic schema. Similarly, psychotropic treatments ranging from lithium and antipsychotics to serotonin reuptake inhibitors (SSRIs) and acetylcholinesterase inhibitors have been shown to be efficacious in a wide spectrum of psychiatric disorders ranging from autism, schizophrenia (SZ), depression, and bipolar disorder (BD) to Alzheimer's disease (AD). This apparent lack of specificity suggests that psychiatric symptoms as well as treatments may share aspects of pathophysiology and mechanisms of action that defy current symptom-based diagnostic and neuron-based therapeutic schema. A myelin-centered model of human brain function can help integrate these incongruities and provide novel insights into disease etiologies and treatment mechanisms. Available data are integrated herein to suggest that widely used psychotropic treatments ranging from antipsychotics and antidepressants to lithium and electroconvulsive therapy share complex signaling pathways such as Akt and glycogen synthase kinase-3 (GSK3) that affect myelination, its plasticity, and repair. These signaling pathways respond to neurotransmitters, neurotrophins, hormones, and nutrition, underlie intricate neuroglial communications, and may substantially contribute to the mechanisms of action and wide spectra of efficacy of current therapeutics by promoting myelination. Imaging and genetic technologies make it possible to safely and non-invasively test these hypotheses directly in humans and can help guide clinical trial efforts designed to correct myelination abnormalities. Such efforts may provide insights into novel avenues for treatment and prevention of some of the most prevalent and devastating human diseases.
    Neuropharmacology 01/2012; 62(7):2137-53. DOI:10.1016/j.neuropharm.2012.01.015 · 5.11 Impact Factor
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    • "In contrast, lower GSK3β expression was reported in prefrontal cortex of teenage suicide victims (Pandey et al., 2009). There is also evidence of fluctuations in the inhibitory serine-phosphorylation of GSK3 in peripheral blood mononuclear cells, generally with decreases associated with disease and increases following therapy (Li et al., 2007b, 2010). These findings suggest that it may be possible to develop measurements of phosphorylated GSK3 as a biomarker to reflect disease state and/or treatment responses. "
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    ABSTRACT: The mood disorders major depressive disorder and bipolar disorder are prevalent, are inadequately treated, and little is known about their etiologies. A better understanding of the causes of mood disorders would benefit from improved animal models of mood disorders, which now rely on behavioral measurements. This review considers the limitations in relating measures of rodent behaviors to mood disorders, and the evidence from behavioral assessments indicating that glycogen synthase kinase-3 (GSK3) dysregulation promotes mood disorders and is a potential target for treating mood disorders. The classical mood stabilizer lithium was identified by studying animal behaviors and later was discovered to be an inhibitor of GSK3. Several mood-relevant behavioral effects of lithium in rodents have been identified, and most have now been shown to be due to its inhibition of GSK3. An extensive variety of pharmacological and molecular approaches for manipulating GSK3 are discussed, the results of which strongly support the proposal that inhibition of GSK3 reduces both depression-like and manic-like behaviors. Studies in human postmortem brain and peripheral cells also have identified correlations between alterations in GSK3 and mood disorders. Evidence is reviewed that depression may be associated with impaired inhibitory control of GSK3, and mania by hyper-stimulation of GSK3. Taken together, these studies provide substantial support for the hypothesis that inhibition of GSK3 activity is therapeutic for mood disorders. Future research should identify the causes of dysregulated GSK3 in mood disorders and the actions of GSK3 that contribute to these diseases.
    Frontiers in Molecular Neuroscience 08/2011; 4:16. DOI:10.3389/fnmol.2011.00016 · 4.08 Impact Factor
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