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IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity.

Cryns K, Shamir A, Van Acker N, Levi I, Daneels G, Goris I, Bouwknecht JA, Andries L, Kass S, Agam G, Belmaker H, Bersudsky Y, Steckler T, Moechars D

1Research and Early Development Europe, Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium.

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.Neuropsychopharmacology (2008) 33, 674-684; doi:10.1038/sj.npp.1301431; published online 25 April 2007.

Published 14 January 2008 in Neuropsychopharmacology, 33(3): 674-84.
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