1. ¹Research and Early Development Europe, Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium
2. ²Stanley Research Center, Faculty of Health Sciences, Ben Gurion University of the Negev and Mental Health Center, Beer-Sheva, Israel
3. ³Histogenex, Antwerp, Belgium

Correspondence: Dr D Moechars, Research and Early Development Europe, Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium. Tel: +32 14 605915; Fax: +32 14 606111; E-mail: dmoechar@prdbe.jnj.com

⁴These authors contributed equally to this work.

Received 11 September 2006; Revised 9 March 2007; Accepted 12 March 2007; Published online 25 April 2007.

Abstract

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.