Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium.
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-3beta (Gsk-3beta), 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-3beta+/- 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-3beta in mediating behavioral responses to lithium.
Division of Hematology-Oncology, Department of Medicine, and Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6148, USA.
W Timothy
WT
O'Brien
Amber DeAra
AD
Harper
Fernando
F
Jové
James R
JR
Woodgett
Silvia
S
Maretto
Stefano
S
Piccolo
Peter S
PS
Klein
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000201:enzymology*; D001923:Brain Chemistry / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006120:Grooming / Q000187:drug effects; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D006579:Heterozygote; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D018021:Lithium Chloride / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011619:Psychotropic Drugs / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D013216:Reflex, Startle / Q000187:drug effects; D012919:Social Behavior; D013550:Swimming; D015534:Trans-Activators / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects; D051153:Wnt Proteins; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011619:Psychotropic Drugs; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride