Valproate regulates GSK-3-mediated axonal remodeling and synapsin I clustering in developing neurons

Mol Cell Neurosci. 2002 Jun;20(2):257-70. doi: 10.1006/mcne.2002.1117.


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-3beta, a serine/threonine kinase involved in the insulin and WNT signaling pathways. Inhibition of GSK-3beta 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-3beta-phosphorylated form of MAP-1B in developing neurons, suggesting that therapeutic concentrations of these mood stabilizers inhibit GSK-3beta. In vitro kinase assays show that therapeutic concentrations of VPA do not inhibit GSK-3beta but that therapeutic concentrations of lithium partially inhibit GSK-3beta activity. Our results support the idea that both mood stabilizers inhibit GSK-3beta in developing neurons through different pathways. Lithium directly inhibits GSK-3beta in contrast to VPA, which inhibits GSK-3beta indirectly by an as-yet-unknown pathway. These findings may have important implications for the development of new strategies to treat bipolar disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Antimanic Agents / pharmacology*
  • Axons / drug effects*
  • Axons / metabolism
  • Axons / ultrastructure
  • Brain / cytology
  • Brain / drug effects*
  • Brain / growth & development
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Differentiation / drug effects*
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Drug Interactions / physiology
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase Kinase 3
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases / metabolism
  • Lithium / pharmacology
  • Mice
  • Microtubule-Associated Proteins / drug effects
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / drug effects
  • Microtubules / metabolism
  • Nerve Fibers / drug effects
  • Nerve Fibers / metabolism
  • Nerve Fibers / ultrastructure
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / physiology
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Synapsins / drug effects*
  • Synapsins / metabolism
  • Valproic Acid / pharmacology*
  • Wnt Proteins


  • Antimanic Agents
  • Drug Combinations
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins
  • Synapsins
  • Wnt Proteins
  • Wnt7a protein, mouse
  • microtubule-associated protein 1B
  • Valproic Acid
  • Lithium
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3
  • Histone Deacetylases