Classical monoamine hypothesis of depression implies a decrease in brain neurotransmitters as serotonin and noradrenaline, which are increased after chronic antidepressant treatment. New hypotheses suggest the impairment of neuroproliferative/neuroplastic pathways involved in these diseases, which are upregulated by the use of antidepressants. However, although animal models have been extensively studied, few data have been reported in the same set of human brain samples regarding the activation level of these diverse pathways. Here we have studied the protein and mRNA expression of the neurotrophic factor BDNF, the activation of Wnt/ß-catenin pathway (GSK3ß phosphorylation and ß-catenin levels), and mTOR pathway activation (mTOR and 4EBP1 phosphorylation) in frontal cortex from human brain samples dissected at autopsy from 16 suicide victims and 16 control subjects. In Wnt/ ß-catenin pathway, we found a significant decrease in ß-catenin protein level in brain samples from depressed suicide free of antidepressant treatment (AD-free group) compared to control group (p<0.01), but not in the samples from depressed suicide with antidepressant treatment (AD-treated group). ß-catenin mRNA levels were no changed in the different groups. In addition, the phosphorylation of GSK-3ß (Ser9) (ratio p-GSK-3ß/GSK-3ß), was significantly increased in AD-treated group compared to controls (p<0.05) and AD-free groups (p<0.05). Regarding mTOR pathway activation, mTOR phosphorylation (ratio p-mTOR/mTOR) was increased in brain samples from AD-treated group compared to control (p<0.05) and AD-free groups (p<0.05). In parallel to this increased activation, a clear tendency to the increase of mTOR mRNA levels in AD-treated group compared to the other groups was observed. In addition, we found a decrease in the phosphorylation of 4E-BP1 protein (ratio p-4E-BP1/4E-BP1) in brain samples from depressed suicide. A reduction in mRNA levels was also observed for AD-treated (p<0.05) and AD-free groups (p<0.05) compared to control group. In addition, BDNF levels were also decreased in AD-free group (p<0.05 vs the control group) as previously reported, with a partial recovery of this neurotrophic factor level after antidepressant treatment. These results indicate the impairment of neuroproliferative/neuroplastic pathways as Wnt/ß-catenin and BDNF in major depression. These pathways are partially restored after antidepressant treatment, together with the activation of the mTOR pathway.

Resumen del póster presentado al Meeting Neuroscience 2014, celebrado en Washington DC (US) del 15 al 19 de noviembre de 2014.

Ministry of Science (SAF07-61862) and Ministry of Economy and Competitivity (SAF2011-25020).

Peer Reviewed