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

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 IMPA I gene (IMPAI -/- ) to study the in vivo physiological functions of IMPA I, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPAI -/- mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA I in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPAI -/- 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 IMPAI -/- 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 IMPA I represents a physiologically relevant target for lithium. In conclusion the IMPAI -/- mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPAI can mimic some actions of lithium.