Genetic alterations in the aetiology of depression

Studenteropgave: Kandidatspeciale og HD afgangsprojekt

  • Anne Flou Kristensen
In Denmark approximately 3 % suffers from moderate to severe depression, and worldwide this number exceeds more than 100 million people. Very little is known about the pathophysiology of depression, and to date researches have not been able to identify a single gene or a single brain structure which can be the reason for depressive behaviour. Though it has been found that many brain structures and genes are affected by the disease and the complex pathophysiology of depression involves alterations of several different neural circuits. The symptomatology of depression thus goes beyond depressed mood and covers clinically significant weight gain/loss, insomnia or hypersomnia, fatigue or loss of energy, feelings of worthlessness or excessive guilt, and recurrent thoughts of death or suicide. During the resent years not much has happened in the treatment area and since the 1950'ties, where two types of antidepressants were discovered, no new strategies or novel treatments have been found. The tricyclic antidepressants and the monoamine oxidase inhibitors were coincidently found to be effective as anti-depressive agents. Though the side-effect profile of these antidepressants have improved, the present treatment still remains sub-optimal. Unfortunately, in order to discover any novel treatment strategies, a more comprehensive knowledge of the underlying genetic mechanisms resulting in depression is needed.
Through this study, the commonly used Chronic Mild Stress (CMS) animal model of depression and the novel animal model of Maternal Separation (MS) will be subjects of an expression analysis, where 13 genes will be investigated. These genes include four subunits of the AP-1 complex; c-Jun, c-Fos, FosB, and JunB, two downstream targets of the AP-1 complex; Galanin (Gal) and Neuropeptide Y (NPY). Furthermore, was the whole Glucocorticoid Receptor (GR) expression investigated and the fraction of GR containing exon 17 was also included. Two plasticity related genes; Activity-Regulated Cytoskeleton associated protein (Arc) and Regulating Synaptic Membrane Exocytosis-1α (Rims1α), and three other genes; cAMP Response Element-Binding protein (CREB), DNA Methyltransferase -3a (DNMT3a) and Glutamic Acid Decarboxylase-1 (GAD1) were also included in the assay. The expression of all genes were investigated in five different experimental animal groups; control group, MS anhedonic group, CMS anhedonic group, MS/CMS anhedonic group and MS/CMS resilient group. All genes are related to depressive behaviour through different functions of the hippocampus. Glucocorticoid Receptor exon 17 was further investigated for methylations at the promoter region, which was accomplished through sodium bisulfite treatment of DNA and thereafter sequencing of DNA. Lastly an optimization of a Native Chrommatin Immunoprecipitation protocol was initiated.
Interestingly, it was found that both the CMS and MS paradigm had an effect on expression of all genes. Especially the effect of the animal models on subunits c-Fos, FosB and JunB is interesting as the expression of these three genes were similar. Moreover, CMS and MS seemed to have distinct effects on the expression of some of the genes, indicating that though the animals shared an anhedonic profile, the underlying genetic alteration might be different. Moreover, the expression of all genes except c-Jun was higher in the MS/CMS resilient group compared to the MS/CMS anhedonic group, which indicates that the genotypic response of the MS/CMS resilient animals differ from that of the MS/CMS anhedonic animals.
Antal sider54
ID: 73768231