title: Knockout mice in understanding the mechanism of action of lithium.
abstract: Lithium inhibits IMPase (inositol monophosphatase) activity, as well as inositol transporter function. To determine whether one or more of these mechanisms might underlie lithium's behavioural effects, we studied Impa1 (encoding IMPase) and Smit1 (sodium-myo-inositol transporter 1)-knockout mice. In brains of adult homozygous Impa1-knockout mice, IMPase activity was found to be decreased; however, inositol levels were not found to be altered. Behavioural analysis indicated decreased immobility in the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures. These are behaviours robustly induced by lithium. In homozygous Smit1-knockout mice, free inositol levels were decreased in the frontal cortex and hippocampus. These animals behave like lithium-treated animals in the model of pilocarpine seizures and in the Porsolt forced-swim test model of depression. In contrast with O'Brien et al. [O'Brien, Harper, Jove, Woodgett, Maretto, Piccolo and Klein (2004) J. Neurosci. 24, 6791-6798], we could not confirm that heterozygous Gsk3b (glycogen synthase kinase 3beta)-knockout mice exhibit decreased immobility in the Porsolt forced-swim test or decreased amphetamine-induced hyperactivity in a manner mimicking lithium's behavioural effects. These data support the role of inositol-related processes rather than GSK3beta in the mechanism of the therapeutic action of lithium.
authors.affiliation: Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel. galila@bgu.ac.il
authors.forename: Galila
authors.initials: G
authors.lastname: Agam
authors.forename: Yuly
authors.initials: Y
authors.lastname: Bersudsky
authors.forename: Gerard T
authors.initials: GT
authors.lastname: Berry
authors.forename: Diederik
authors.initials: D
authors.lastname: Moechars
authors.forename: Yael
authors.initials: Y
authors.lastname: Lavi-Avnon
authors.forename: R H
authors.initials: RH
authors.lastname: Belmaker
mesh_terms: D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D007294:Inositol / Q000378:metabolism; D018020:Lithium Compounds / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D009483:Neuropsychological Tests; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism
chemical_list: D018692:Antimanic Agents; D018020:Lithium Compounds; C508355:SLC5A3 protein, mouse; D027981:Symporters; D007294:Inositol; D038362:Glycogen Synthase Kinase 3; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase