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 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.
Cryns
Kim
K
Research and Early Development Europe, Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium.
Shamir
Alon
A
Van Acker
Nathalie
N
Levi
Itzhak
I
Daneels
Guy
G
Goris
Ilse
I
Bouwknecht
J Adriaan
JA
Andries
Luc
L
Kass
Stefan
S
Agam
Galila
G
Belmaker
Haim
H
Bersudsky
Yuly
Y
Steckler
Thomas
T
Moechars
Dieder
D
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
D018692:Antimanic Agents; D018721:Muscarinic Agonists; D010862:Pilocarpine; D016651:Lithium Carbonate; D007294:Inositol; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase