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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    • "GSK-3 is constitutively activated and its phosphorylation at Ser-9 is a step whereby multiple protective signaling pathways converge (Gould and Manji, 2005). Levels of phospho-Ser9-GSK-3beta in BD patients treated with lithium are higher than in healthy controls (Li et al., 2010). In the present study, lithium prevented AMPHinduced alterations in phospho-GSK-3beta, whereas CDS lacked such effects. "
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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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    • "—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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