Implication of Wnt /β-catenin pathway in affective disorders

Abstract

Psychiatric disorders such as major depression and schizophrenia affect to 25% of the population. Recently, the Wnt /βcatenin pathway has been involved in cell proliferation processes induced by antidepressant drugs. Activation of canonical Wnt pathway results in the inhibition of GSK3β kinase activity, thereby stabilizing β-catenin in the cytosol and thus increasing its translocation to the nucleus, where it promotes the transcription of target genes such as c myc and cyclin D1. It is possible that antidepressants modulate these complex signaling systems and the interconnections among them. The identification of a specific signaling pathway as a target of therapeutic action of antidepressants supports the possible role of this pathway in the pathogenesis of depression. Our work is based on the study of cell proliferation markers in samples of human frontal cortex post mortem tissue samples from suicide victims (n = 39) with an ante mortem clinical history of major depression, and their corresponding control cases (n = 39) with no record of psychiatric illness. These samples were matched for sex, age and the postmortem delay (defined as the time elapsed between the death of the individual and the freezing of the samples in hours). All cases were subjected to toxicological tests to determine the presence of drugs in the body at the time of death. In the case of samples from subjects with major depression a significant decrease in the protein expression levels of β-catenin (40%, p <0,05) and AKT (27%, p <0,05) was found, without differences between the antidepressant free and antidepressant treated subjects. In order to found a peripheral marker of Wnt/β-catenin pathway, we genotyped two different SNP of β-catenin. The genotyping studies of β-catenin were carried out in 98 patients with major depression and 334 control subjects without clinical evidence of psychiatric disorders was. Genotyping experiments were performed in all patients and controls for β-catenin polymorphisms (rs4135385 and rs3864004 in the region exon 3) by allelic discrimination assay for PCR reaction (polymerase chain) with commercial probes (TaqMan ® SNP Genotyping Assays). The most significantly associated SNP was rs4135385 (P <0,0001) Our data demonstrate the existence of an alteration in the signaling pathway of β-catenin in major depression, a protein involved in proliferation processes, thus supporting the neurodegenerative hypothesis of depression.