Convergence of glycogen synthase kinase 3 beta and GR signaling in response to fluoxetine treatment in chronically stressed female and male rats
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Accumulating evidence strongly suggest that impaired glucocorticoid receptor (GR) signaling is involved in stress-related mood disorders, and nominate GR as a potential target for antidepressants (ADs). It is known that different classes of ADs affects the GR action via modifying its phosphorylation, while the mechanism through which ADs alter GR phosphorylation targeted by GSK3 beta, a kinase modulated via serotonin neurotransmission, are unclear. On this basis, we investigated whether GSK3 beta-GR signaling could be a convergence point of fluoxetine action on brain function and behavior, by examining its effect on GSK3 beta targeted-GR phosphorylation on threonine 171 (pGR171), and expression of GR-regulated genes in the hippocampus of female and male rats exposed to chronic isolation stress. Stress induced sex-specific GSK3 beta-targeted phosphorylation of pGR171 in the nucleus of the hippocampus of stressed animals. Namely, while in females stress triggered coupled action of GSK3 b...eta-pGR171 signaling, in males changes in pGR171 levels did not correspond to GSK3 beta activity. On the other hand, fluoxetine managed to up regulate this pathway in sex-unbiased manner. Furthermore, fluoxetine reverted stress-induced changes in most of the analyzed genes in males, CRH, 5-HT1a and p11, while in females its effect was limited to CRH. These data further suggest that pGR171 signaling affects cellular localization of GR in response to chronic stress and fluoxetine in both sexes. Collectively, our results describe a novel convergence point between GR signaling and GSK3 beta pathway in rat hippocampus in response to stress and fluoxetine in both sexes and its involvement in fluoxetine-regulated brain function in males.