GLYCOGEN SYNTHASE KINASE

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.