Glycogen Synthase Kinase-3β: Variation over Time and the Possible Association with Mood and Cognition in Healthy Individuals

Abstract

Evidence indicates a role for glycogen synthase kinase-3β (GSK-3β) in the pathophysiology of mood disorders and in cognitive disturbances; however, the natural variation in GSK-3β activity over time is unknown. We aimed to investigate GSK-3β activity over time and its possible correlation with emotional lability, subjective mood fluctuations and cognitive function in healthy individuals. Thirty-seven healthy subjects were evaluated with neuropsychological tests and blood samples at baseline and 12-week follow-up. Total GSK-3β and serine-9-phosphorylated GSK-3β in peripheral blood mononuclear cells were quantitated using enzyme immunometric assays. The activity of GSK-3β (serine-9-phosphorylated GSK-3β/total GSK-3β) was lower at baseline compared with follow-up. No significant mean change over time was observed in levels of total GSK-3β and serine-9-phosphorylated GSK-3β. Exploratory analysis revealed lower activity of GSK-3β in spring and summer compared with the fall season. No correlation was observed between GSK-3β activity and emotional lability, subjective mood fluctuations or cognitive function. The results suggest that intra- and interindividual variation in GSK-3β activity over time could contribute to the heterogeneity of findings in clinical studies. The stability of GSK-3β activity and the role of potential moderators of GSK-3β activity warrant further investigation. Clinical studies of GSK-3β should consider including repeated measures of both cases and healthy individuals.

Glycogen synthase kinase‐3β in patients with bipolar I disorder: results from a prospective study

“…As in other studies, we investigated the activity of GSK‐3β in PBMCs as a surrogate system as the regulation of the expression of receptors, enzymes and intracellular proteins in lymphocytes in PBMCs share many similarities with that in brain neurons . While there is no clear evidence that the changes found in PBMCs mirror alterations in signaling pathways in brain neurons, multiple biological processes that may also include GSK‐3β and related signaling pathways are similar in PBMCs and the brain .…”

“…Thus, overall, it seems likely that at least part of the divergence in the findings is due to the varying prevalence of different affective states in the included study samples. Another issue that may contribute to the variation in results between studies is that no other study included a longitudinal assessment of the healthy control subjects; thus, among the healthy control subjects included in the present study, the GSK‐3β ratio increased from baseline to the three‐month follow‐up, as previously reported by Munkholm et al (whereas there was no difference in total GSK‐3β, p‐GSK‐3β) . In fact, only a couple studies on potential biomarkers in mood disorders have included longitudinal assessment of control subjects …”

“…to be more informative, but even this ratio is an indirect measure of GSK‐3β activity. In the present study, we included all three measures of GSK‐3β levels, as also done in the study by Ladeira et al., but we primarily hypothesized changes in p‐GSK‐3β as this parameter was used in most prior studies, and also because this is a direct measure of GSK activity.…”

“…As in several other studies, blood was withdrawn following 8–10 hours of fasting. As GSK‐3β is tightly involved in carbohydrate metabolism, this might have introduced a bias.…”

“…The conflicting results may be due to different and small patient populations as well as differences in the prevalence of affective states (manic, mixed, depressive, or euthymic). Further, we have previously revealed intra‐ and interindividual variation in GSK‐3β activity over time in healthy subjects, so, as no prior study has included repeated measures of GSK‐3β, this could further contribute to the heterogeneity of the findings . We suggest that clinical studies of GSK‐3β should include repeated measures of cases and healthy subjects alike as we have in studies of other potential biomarkers in bipolar disorder and as emphasized by others…”