Glycogen synthase kinase-3 levels and phosphorylation undergo large fluctuations in mouse brain during development.

OBJECTIVES

Dysregulated glycogen synthase kinase-3 (GSK3) may contribute to the pathophysiology of mood disorders and other diseases, and appears to be a target of certain therapeutic drugs. The growing recognition of heightened vulnerability during development to many psychiatric diseases, including mood disorders, led us to test if there are developmental changes in mouse brain GSK3 and its regulation by phosphorylation and by therapeutic drugs.

METHODS

GSK3 levels and phosphorylation were measured at seven ages of development in the mouse cerebral cortex and hippocampus.

RESULTS

Two periods of rapid transitions in GSK3 levels were identified: a large rise between postnatal days 1 and 2 and three weeks of age, where GSK3 levels were as much as fourfold higher than adult mouse brain levels, and a rapid decline between 2-4 and eight weeks of age, when adult levels were reached. Inhibitory serine-phosphorylation of GSK3, particularly GSK3β, was extremely high in the one-day postnatal mouse brain, and rapidly declined thereafter. These developmental changes in GSK3 were equivalent in the male and female cerebral cortex, and differed from other signaling kinases, including Akt, extracellular-regulated kinases 1/2, c-Jun N-terminal kinase, and p38 levels and phosphorylation. In contrast to the adult mouse brain, where administration of lithium or fluoxetine rapidly and robustly increased serine-phosphorylation of GSK3, in young mice these responses were blunted or absent.

CONCLUSIONS

High brain levels of GSK3 and large fluctuations in its levels and phosphorylation in the juvenile and adolescent mouse brain raise the possibility that they may contribute to destabilized mood regulation induced by environmental and genetic factors.