Lack of lithium-like behavioral and molecular effects in IMPA2 knockout mice.
Lithium is a potent mood-stabilizing medication in bipolar disorder. Despite 50 years of clinical use, the mechanism of action is unknown. Multiple effects have been attributed to lithium including the uncompetitive inhibition of inositol monophosphatase (IMPase). IMPA2, one of the genes that encode IMPase, is located in a region with linkage to bipolar disorder. Owing to the role of IMPase in cell signaling and the possibility that this enzyme is a target for mood-stabilizing drugs, we generated IMPA2(-/-) mice. Possible involvement of IMPase in complex behaviors related to affective disorders was assessed by monitoring the behavior of the IMPA2(-/-) mice in the forced swim test, the tail suspension test (TST), the elevated zero-maze and open field test. It has been described that chronically lithium-treated mice exhibit reduced immobility time in the forced swim test and decreased exploratory behavior. We found increased rearing of IMPA2(-/-) mice in the open field, suggesting an increased exploratory behavior. Although immobility time of IMPA2(-/-) female but not male mice in the forced swim test was reduced, no difference was found between male and female IMPA2(-/-) and IMPA2(+/+) mice in the TST and overall there was no clear effect of the deletion of IMPA2 on depression-like behavior. Frontal cortex IMPase activity and inositol levels in the IMPA2(-/-) mice did not differ from IMPA2(+/+) mice, but kidney inositol levels were reduced. In conclusion, phenotypic characterization of the IMPA2(-/-) mouse indicates that deleting IMPA2 does not mimic the effects of lithium treatment.
Cryns
Kim
K
Research and Early Development Europe, Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium. kcryns@prdbe.jnj.com
Shamir
Alon
A
Shapiro
Joseph
J
Daneels
Gie
G
Goris
Ilse
I
Van Craenendonck
Hansfried
H
Straetemans
Roel
R
Belmaker
R H
RH
Agam
Galila
G
Moechars
Dieder
D
Steckler
Thomas
T
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D005106:Exploratory Behavior / Q000502:physiology; D005625:Frontal Lobe / Q000378:metabolism / Q000502:physiology; D015870:Gene Expression / Q000502:physiology*; D019417:Hindlimb Suspension / Q000379:methods; D007294:Inositol / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D013550:Swimming
D000697:Central Nervous System Stimulants; D007294:Inositol; D000324:Adrenocorticotropic Hormone; D000661:Amphetamine; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D003345:Corticosterone