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 3β)-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 GSK3β in the mechanism of the therapeutic action of lithium.
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October 2009
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Conference Article|
September 21 2009
Knockout mice in understanding the mechanism of action of lithium
Galila Agam;
Galila Agam
1
*Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel
1To whom correspondence should be addressed (email galila@bgu.ac.il).
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Yuly Bersudsky;
Yuly Bersudsky
*Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel
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Gerard T. Berry;
Gerard T. Berry
†Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, U.S.A.
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Diederik Moechars;
Diederik Moechars
‡Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340, Beerse, Belgium
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Yael Lavi-Avnon;
Yael Lavi-Avnon
*Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel
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R.H. Belmaker
R.H. Belmaker
*Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel
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Publisher: Portland Press Ltd
Received:
April 13 2009
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem Soc Trans (2009) 37 (5): 1121–1125.
Article history
Received:
April 13 2009
Citation
Galila Agam, Yuly Bersudsky, Gerard T. Berry, Diederik Moechars, Yael Lavi-Avnon, R.H. Belmaker; Knockout mice in understanding the mechanism of action of lithium. Biochem Soc Trans 1 October 2009; 37 (5): 1121–1125. doi: https://doi.org/10.1042/BST0371121
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