SMIT1 haploinsufficiency causes brain inositol deficiency without affecting lithium-sensitive behavior

Alona Shaldubina, Roy A. Johanson, W. Timothy O'Brien, Roberto Buccafusca, Galila Agam, R. H. Belmaker, Peter S. Klein, Yuly Bersudsky, Gerard T. Berry

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Two leading hypotheses to explain lithium action in bipolar disorder propose either inositol depletion or inhibition of GSK-3 as mechanisms of action. Behavioral effects of lithium are mimicked in Gsk-3β+/- mice, but the contribution of inositol depletion to these behaviors has not been tested. According to the inositol depletion hypothesis, lithium-sensitive behavior is secondary to impaired phosphatidylinositol synthesis caused by inositol deficiency. By disrupting the sodium myo-inositol transporter1 gene, SMIT1, we show that depletion of brain myo-inositol in SMIT1+/- mice has no effect on lithium-sensitive behavior. These findings, taken together with our previous work showing that SMIT-/- mice have an even greater depletion of inositol in brain with no reduction in phosphatidylinositol levels, are difficult to reconcile with the current formulation of the inositol depletion hypothesis.

Original languageEnglish
Pages (from-to)384-388
Number of pages5
JournalMolecular Genetics and Metabolism
Issue number4
StatePublished - 1 Aug 2006


  • Behavior
  • Bipolar disorder
  • GSK-3
  • Inositol
  • Inositol monophosphatase (IMPase)
  • Lithium
  • SMIT1

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


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