Lithium and synaptic plasticity

Bipolar Disord. 1999 Dec;1(2):87-90. doi: 10.1034/j.1399-5618.1999.010205.x.


Lithium, a small cation, has been used in the treatment of bipolar disorders since its introduction in the 1950s by John Cade. Extensive research on the mechanism of action of lithium has revealed several possible targets. For some time, the most widely accepted action of lithium was its inhibitory effect on the synthesis of inositol, resulting in depletion of inositol with profound effects on neuronal signal transduction pathways. However, several studies show that some effects of lithium are not mediated through inositol depletion. Recent findings demonstrate that lithium directly inhibits, in a non-competitive fashion, the activity of glycogen synthase kinase (GSK)-3beta, a serine/threonine kinase highly expressed in the central nervous system. Interestingly, inhibition of GSK-3beta has been shown to regulate neuronal plasticity by inducing axonal remodelling and increasing the levels of synaptic proteins. These findings raise the possibility for developing new therapeutic approaches for the treatment of bipolar disorders.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antimanic Agents / pharmacology*
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / enzymology*
  • Bipolar Disorder / physiopathology
  • Brain Chemistry
  • Calcium-Calmodulin-Dependent Protein Kinases / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • GAP-43 Protein / drug effects
  • GAP-43 Protein / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Humans
  • Inositol / metabolism
  • Lithium Compounds / pharmacology*
  • Neuronal Plasticity* / drug effects
  • Protein Kinase C / drug effects
  • Protein Kinase C / metabolism


  • Antimanic Agents
  • GAP-43 Protein
  • Lithium Compounds
  • Inositol
  • Glycogen Synthase Kinases
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3