IMPA1 is essential for embryonic development and lithium-like pilocarpine sensitivity

Neuropsychopharmacology. 2008 Feb;33(3):674-84. doi: 10.1038/sj.npp.1301431. Epub 2007 Apr 25.


Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1-/-) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1-/- mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1-/- mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1-/- mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1-/- mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.

MeSH terms

  • Animals
  • Antimanic Agents / pharmacology*
  • Behavior, Animal / drug effects
  • Body Weight / drug effects
  • Chromatography, Gas
  • Drinking / drug effects
  • Embryonic Development / genetics*
  • Inositol / deficiency
  • Inositol / pharmacology
  • Lithium Carbonate / pharmacology*
  • Male
  • Mice
  • Mice, Knockout
  • Motor Activity / drug effects
  • Muscarinic Agonists / pharmacology*
  • Mutagenesis
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism
  • Pilocarpine / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Swimming / psychology


  • Antimanic Agents
  • Muscarinic Agonists
  • Pilocarpine
  • Lithium Carbonate
  • Inositol
  • Phosphoric Monoester Hydrolases
  • myo-inositol-1 (or 4)-monophosphatase