Elucidating the functions of brain GSK3-alpha: Possible synergy with GSK3-beta upregulation and reversal by antidepressant treatment in a mouse model of depressive-like behaviour

Glycogen synthase kinase 3 (GSK3) has been linked to the mechanisms of stress, mood regulation, and the effects of antidepressants. The functions of the GSK3 beta isoform have been extensively investigated, but little is known about the a-isoform, although they may functionally related. In a recently established modified swim test with a third delayed swim exposure, brain GSK3 beta mRNA expression positively correlated with floating behaviour on the third test. A two-week-long pretreatment regime with imipramine (7.5 mg/kg/day) or thiamine (200 mg/kg/ day), which is known to have antidepressant properties, reduced the GSK3 beta over-expression and decreased floating behaviour on Day 5. GSK3 alpha mRNA levels were measured in the hippocampus and prefrontal cortex on Days 1, 2 and 5. GSK3 alpha expression was decreased in the prefrontal cortex on Day 2 and increased on Day 5. In this model, GSK3 alpha mRNA changes were prevented by imipramine or thiamine treatment. There was a significant correlation between the expression of the two isoforms in the prefrontal cortex on Day 2 in untreated group. These results provide the first evidence for the potential involvement of GSK3 alpha in depressive-like behaviours and as a target of anti-depressant therapy. Furthermore, the correlations suggest some cross-talk may exist between the two GSK3 isoforms.