 |
The Journal of Neuroscience, July 28, 2004, 24(30):6791-6798; doi:10.1523/JNEUROSCI.4753-03.2004
 Previous Article | Next Article 
Behavioral/Systems/Cognitive
Glycogen Synthase Kinase-3 Haploinsufficiency Mimics the Behavioral and Molecular Effects of Lithium
W. Timothy O'Brien,1
Amber DeAra Harper,1
Fernando Jové,1
James R. Woodgett,2
Silvia Maretto,3
Stefano Piccolo,3 and
Peter S. Klein1
1Division of Hematology-Oncology, Department of Medicine, and Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6148, 2Ontario Cancer Institute, Toronto, Ontario, Canada M5G 2M9, and 3Histology and Embryology Section, Department of Histology, Microbiology, and Medical Biotechnology, University of Padua, 35131 Padua, Italy
Lithium is widely used to treat bipolar disorder, but its mechanism of action in this disorder is unknown. Several molecular targets of lithium have been identified, but these putative targets have not been shown to be responsible for the behavioral effects of lithium in vivo. A robust model for the effects of chronic lithium on behavior in mice would greatly facilitate the characterization of lithium action. We describe behaviors in mice that are robustly affected by chronic lithium. Remarkably, these lithium-sensitive behaviors are also observed in mice lacking one copy of the gene encoding glycogen synthase kinase-3 (Gsk-3), a well established direct target of lithium. In addition, chronic lithium induces molecular changes consistent with inhibition of GSK-3 within regions of the brain that are paralleled in Gsk-3+/- heterozygous mice. We also show that lithium therapy activates Wnt signaling in vivo, as measured by increased Wnt-dependent gene expression in the amygdala, hippocampus, and hypothalamus. These observations support a central role for GSK-3 in mediating behavioral responses to lithium.
Key words: amygdala; behavior; lithium; glycogen synthase kinase 3; GSK-3; Wnt; T-cell factor (TCF); bipolar disorder; forced swim test; mouse
Received Oct 21, 2003;
revised June 10, 2004;
accepted June 18, 2004.
This article has been cited by other articles:
|
|
|
|
 
P. P. Zandi, P. L. Belmonte, V. L. Willour, F. S. Goes, J. A. Badner, S. G. Simpson, E. S. Gershon, F. J. McMahon, J. R. DePaulo Jr, J. B. Potash, et al.
Association Study of Wnt Signaling Pathway Genes in Bipolar Disorder
Arch Gen Psychiatry,
July 1, 2008;
65(7):
785 - 793.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. H. Belmaker, G. Agam, and Y. Bersudsky
Role of GSK3{beta} in behavioral abnormalities induced by serotonin deficiency
PNAS,
May 20, 2008;
105(20):
E23 - E23.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-M. Beaulieu, X. Zhang, R. M. Rodriguiz, T. D. Sotnikova, W. C. Wetsel, R. R. Gainetdinov, and M. G. Caron
Reply to Belmaker et al.: GSK3{beta} haploinsufficiency results in lithium-like effects in the forced-swim test
PNAS,
May 20, 2008;
105(20):
E24 - E24.
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Li, S. August, and D. S. Woulfe
GSK3{beta} is a negative regulator of platelet function and thrombosis
Blood,
April 1, 2008;
111(7):
3522 - 3530.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Leng, M.-H. Liang, M. Ren, Z. Marinova, P. Leeds, and D.-M. Chuang
Synergistic Neuroprotective Effects of Lithium and Valproic Acid or Other Histone Deacetylase Inhibitors in Neurons: Roles of Glycogen Synthase Kinase-3 Inhibition
J. Neurosci.,
March 5, 2008;
28(10):
2576 - 2588.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Hongisto, J. C. Vainio, R. Thompson, M. J. Courtney, and E. T. Coffey
The Wnt Pool of Glycogen Synthase Kinase 3{beta} Is Critical for Trophic-Deprivation-Induced Neuronal Death
Mol. Cell. Biol.,
March 1, 2008;
28(5):
1515 - 1527.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. M. Edwards, J. R. Edwards, S. T. Lwin, J. Esparza, B. O. Oyajobi, B. McCluskey, S. Munoz, B. Grubbs, and G. R. Mundy
Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo
Blood,
March 1, 2008;
111(5):
2833 - 2842.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. H. Perlis, S. Purcell, J. Fagerness, A. Kirby, T. L. Petryshen, J. Fan, and P. Sklar
Family-Based Association Study of Lithium-Related and Other Candidate Genes in Bipolar Disorder
Arch Gen Psychiatry,
January 1, 2008;
65(1):
53 - 61.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. W. Wolf, M. Eddison, S. Lee, W. Cho, and U. Heberlein
GSK-3/Shaggy regulates olfactory habituation in Drosophila
PNAS,
March 13, 2007;
104(11):
4653 - 4657.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-H. Liang and D.-M. Chuang
Regulation and Function of Glycogen Synthase Kinase-3 Isoforms in Neuronal Survival
J. Biol. Chem.,
February 9, 2007;
282(6):
3904 - 3917.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-H. Liang and D.-M. Chuang
Differential Roles of Glycogen Synthase Kinase-3 Isoforms in the Regulation of Transcriptional Activation
J. Biol. Chem.,
October 13, 2006;
281(41):
30479 - 30484.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Einat
Modelling facets of mania - new directions related to the notion of endophenotypes
J Psychopharmacol,
September 1, 2006;
20(5):
714 - 722.
[Abstract]
[PDF]
|
|
|
|
|
|
|
P. Clement-Lacroix, M. Ai, F. Morvan, S. Roman-Roman, B. Vayssiere, C. Belleville, K. Estrera, M. L. Warman, R. Baron, and G. Rawadi
Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice
PNAS,
November 29, 2005;
102(48):
17406 - 17411.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Quiroz, T. D. Gould, and H. K. Manji
MOLECULAR EFFECTS of lithium
Mol. Interv.,
October 1, 2004;
4(5):
259 - 272.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
