title: IMPA1 is essential for embryonic development and lithium-like pilocarpine sensitivity.
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.
authors: Research and Early Development Europe, Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium.
authors: Kim
authors: K
authors: Cryns
authors: Alon
authors: A
authors: Shamir
authors: Nathalie
authors: N
authors: Van Acker
authors: Itzhak
authors: I
authors: Levi
authors: Guy
authors: G
authors: Daneels
authors: Ilse
authors: I
authors: Goris
authors: J Adriaan
authors: JA
authors: Bouwknecht
authors: Luc
authors: L
authors: Andries
authors: Stefan
authors: S
authors: Kass
authors: Galila
authors: G
authors: Agam
authors: Haim
authors: H
authors: Belmaker
authors: Yuly
authors: Y
authors: Bersudsky
authors: Thomas
authors: T
authors: Steckler
authors: Dieder
authors: D
authors: Moechars
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002849:Chromatography, Gas; D004326:Drinking / Q000187:drug effects; D047108:Embryonic Development / Q000235:genetics*; D007294:Inositol / Q000172:deficiency / Q000494:pharmacology; D016651:Lithium Carbonate / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology*; D016296:Mutagenesis; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D010862:Pilocarpine / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013550:Swimming / Q000523:psychology
chemical_list: D018692:Antimanic Agents; D018721:Muscarinic Agonists; D010862:Pilocarpine; D016651:Lithium Carbonate; D007294:Inositol; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase