IMPA1 is essential for embryonic development and lithium-like pilocarpine sensitivity.
Neuropsychopharmacology
; 33(3): 674-84, 2008 Feb.
Article
in En
| MEDLINE
| ID: mdl-17460611
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pilocarpine
/
Lithium Carbonate
/
Phosphoric Monoester Hydrolases
/
Muscarinic Agonists
/
Antimanic Agents
/
Embryonic Development
Type of study:
Diagnostic_studies
Limits:
Animals
Language:
En
Journal:
Neuropsychopharmacology
Journal subject:
NEUROLOGIA
/
PSICOFARMACOLOGIA
Year:
2008
Document type:
Article
Affiliation country: