GLYCOGEN SYNTHASE
KINASE-3b
HAPLOINSUFFICIENCY MIMICS THE BEHAVIORAL AND MOLECULAR EFFECTS OF LITHIUM
W.
Timothy O’Brien1, Amber DeAra Haper1, Fernando Jové1,
James R. Woodgett2, Silvia Marettto3, Stefano Piccolo3,
and Peter S. Klein1
1Department of
Medicine (Division of Hematology-Oncology) and Howard Hughes Medical Institute,
University of Pennsylvania School of Medicine; 2Ontario Cancer
Institute, Toronto, ON, Canada; 3Histology and Embryology Section,
Department of Histology, Microbiology and Medial Biotechnology, University of
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 two 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 encode glycogen synthase kinase-3b
(GSK-3b),
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-3b+/-
heterozygous mice. We also show that lithium therapy activates Wnt signaling in
vivo, as measured by increased Wnt-dependent gene expression in the amygdale,
hippocampus, and hypothalamus. These observations support a central role for
GSK-3b
in mediating behavioral responses to lithium.