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. 2012 Dec;14(8):822-30.
doi: 10.1111/bdi.12023.

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

Eléonore Beurel  1 , Marjelo A Mines, Ling Song, Richard S Jope
Affiliations

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

Eléonore Beurel et al. Bipolar Disord. 2012 Dec.

Abstract

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.

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Figures

Fig 1
Fig 1
Developmental changes in total levels of GSK3α and GSK3β in mouse brain. (A) Representative immunoblots and quantitation of total GSK3α and GSK3β in mouse cerebral cortex and hippocampus obtained at postnatal day 1, juveniles at two and three weeks of age, early adolescent at four weeks of age, middle adolescent at six weeks of age, late adolescent at eight weeks of age, and adult at 16 weeks of age. Values shown are relative to values from eight-week-old mice. Means ± standard error (SEM) (n = 4–5). (B) Comparison of male and female levels of GSK3 isoforms in mouse cerebral cortex. Tissue was obtained from male and female mice at three and six weeks of age. Values from female mice are shown relative to those from male mice of the same age. Means ± SEM (n = 4). GSK3 = glycogen synthase kinase-3.
Fig 2
Fig 2
Developmental changes in total levels of extracellular-regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNK), p38, and Akt. Immunoblots of total levels of ERK1/2, JNK, p38, and Akt in mouse cerebral cortex and hippocampus obtained at postnatal day 1, juveniles at two and three weeks of age, early adolescent at four weeks of age, middle adolescent at six weeks of age, late adolescent at eight weeks of age, and adult at 12 and 16 weeks of age. Immunoblots are representative of two independent experiments.
Fig 3
Fig 3
Developmental changes in serine-phosphorylation and tyrosine-phosphorylation of GSK3α and GSK3β in mouse brain. (A) Representative immunoblots and quantitation of phospho-Ser21-GSK3α and phospho-Ser9-GSK3β in mouse cerebral cortex and hippocampus obtained from seven ages of mice. Values shown are ratios of phospho-serine to total GSK3 and are relative to values from eight-week-old mice. Means ± standard error (SEM) (n = 4–5). (B) Representative immunoblots and quantitation of phospho-Tyr279-GSK3α and phospho-Tyr216-GSK3β in mouse cerebral cortex and hippocampus obtained from seven ages of mice. Values shown are ratios of phospho-tyrosine to total GSK3 and are relative to values from eight-week-old mice. Means ± SEM (n = 4–5). GSK3 = glycogen synthase kinase-3.
Fig 4
Fig 4
Comparison of phosphorylation of GSK3 isoforms in male and female mice. (A) Comparison of male and female mouse serine-phosphorylation of GSK3 isoforms in the cerebral cortex at three and six weeks of age. Means ± standard error (SEM) (n = 4). (B) Comparison of male and female mouse tyrosine-phosphorylation of GSK3 isoforms in the cerebral cortex at three and six weeks of age. Values from female mice are shown relative to those from male mice of the same age. Means ± SEM (n = 4). GSK3 = glycogen synthase kinase-3.
Fig 5
Fig 5
Developmental changes in phosphorylation of extracellular-regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNK), p38, and Akt. Representative immunoblots of phosphorylated ERK1/2, JNK, p38, and Akt in mouse cerebral cortex and hippocampus obtained at postnatal day 1, juveniles at two and three weeks of age, early adolescent at four weeks of age, middle adolescent at six weeks of age, late adolescent at eight weeks of age, and adult at 12 and 16 weeks of age. Immunoblots are representative of two independent experiments.
Fig 6
Fig 6
Effects of lithium administration on serine-phosphorylation of GSK3 in mouse brain. Serine-phosphorylation and total levels of GSK3 were measured in three-week-old, five-week-old, and 12-week-old mouse brain regions 0.5, 1.5, and 3.0 hours after administration of 4 mg/kg lithium chloride. Values are presented as percent of untreated mice of the same age. Means ± standard error (SEM) (n = 3) per time point for each age. GSK3 = glycogen synthase kinase-3. *p < 0.05 compared with lithium-free controls of the same age (two-way ANOVA, Bonferroni post-test). **p < 0.05. ††p < 0.07 response to lithium in adult mice compared with young mice (one-way ANOVA).
Fig 7
Fig 7
Effects of fluoxetine administration on serine-phosphorylation of GSK3 in mouse brain. Serine-phosphorylation and total levels of GSK3 were measured in three-week-old, five-week-old, and 12-week-old mouse brain regions 0.5, one, two, and four hours after administration of 20 mg/kg fluoxetine. Values are presented as percent of untreated mice of the same age. Means ± standard error (SEM) (n = 3). GSK3 = glycogen synthase kinase-3. **p < 0.05 response to fluoxetine in adult mice compared with young mice (one-way ANOVA).
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