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Valproate Regulates GSK-3-Mediated Axonal Remodeling and Synapsin I Clustering in Developing Neurons

https://doi.org/10.1006/mcne.2002.1117Get rights and content

Abstract

Valproate (VPA) and lithium have been used for many years in the treatment of manic depression. However, their mechanisms of action remain poorly understood. Recent studies suggest that lithium and VPA inhibit GSK-3β, a serine/threonine kinase involved in the insulin and WNT signaling pathways. Inhibition of GSK-3β by high concentrations of lithium has been shown to mimic WNT-7a signaling by inducing axonal remodeling and clustering of synapsin I in developing neurons. Here we have compared the effect of therapeutic concentrations of lithium and VPA during neuronal maturation. VPA and, to a lesser extent, lithium induce clustering of synapsin I. In addition, lithium and VPA induce similar changes in the morphology of axons by increasing growth cone size, spreading, and branching. More importantly, both mood stabilizers decrease the level of MAP-1B-P, a GSK-3β-phosphorylated form of MAP-1B in developing neurons, suggesting that therapeutic concentrations of these mood stabilizers inhibit GSK-3β. In vitro kinase assays show that therapeutic concentrations of VPA do not inhibit GSK-3β but that therapeutic concentrations of lithium partially inhibit GSK-3β activity. Our results support the idea that both mood stabilizers inhibit GSK-3β in developing neurons through different pathways. Lithium directly inhibits GSK-3β in contrast to VPA, which inhibits GSK-3β indirectly by an as-yet-unknown pathway. These findings may have important implications for the development of new strategies to treat bipolar disorders.

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    1

    Present address: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Berzeliusväg 3, plan 3, BZ-lab, S-17177 Stockholm, Sweden.

    2

    Present address: Eisai London Research Laboratories Limited, Bernard Katz Building, University College London, London WC1E 6BT, United Kingdom.

    3

    To whom correspondence and reprint requests should be addressed at Department of Biological Sciences, Imperial College London, Exhibition Road, London SW7 2AY, United Kingdom. Fax: (44) 20 7594-5207. E-mail: [email protected].

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