Epigenetics in major depression

Epigenetics is more and more recognised as important regulatory mechanisms also in the field of neurobiology. It is primarily an attractive scenario for the explanation of gene-environment interactions. The growing interest in this emerging field is also reflected by the various nomenclatures used to highlight different aspects of the phenomenon, e.g. nature-nurture, environmental (re)programming, etc.. It has been demonstrated that (early) life experience can modulate the stress behaviour in mice throughout their whole lifetime, indicating in particular the involvement of GR. In addition, molecular chaperones have been proposed as mediators of epigenetic events under stressful conditions.

Hence, we started to determine genes that are regulated by glucocorticoid hormones, by a chaperone inhibitor, and by chemicals interfering with enzymes determining the epigenetic marks on the chromosome. Those genes that react both to glucocorticoid and to epigenetic changes will be of prime interest. The techniques include gene expression and ChIP microarrays. These studies should reveal novel candidate genes which will be tested in stress physiology and ageing.

Besides these screening projects, we are focussing on specific targets of epigenetic regulation such as the glutamate transporter. Over the last few years, the neurotransmitter glutamate emerged as an important component in the pathophysiology of major depression. Removal of glutamate from the synaptic cleft serves to terminate glutamate-mediated excitatory neurotransmission and to maintain low resting concentrations of extracellular glutamate. The astroglial glutamate transporter EAAT2 subtype is executing approx. 95% of total glutamate clearance. Pathologically increased levels of glutamate have been reported in the frontal cortex of MDD, BD patients and in suicide victims. Some anti-glutamatergic drugs are in use to enhance the efficacy of conventional antidepressants and exert antidepressant-like effects. A promising novel strategy aims at targeted up-regulation of the glutamate transporter EAAT2 in astrocytes. Therefore, a better understanding of the molecular modes of EAAT2 regulation might help to develop new approaches to restore or improve functional EAAT2 expression.

Fig. 1: Response of EAAT2 expression to drugs targeting the epigenetic status. A-172 glioblastoma cells were exposed to either 5-aza-cytidine (inhibitor of DNA methyltransferase) or trichostatin A (inhibitor of histone deacetylases) separately or in combination. After two days, EAAT2 and actin expression were evaluated by RT-PCR.

In our current studies, we use human as well as rodent cellular systems in order to decipher different aspects of EAAT2/GLT-1 activity. GLT-1 is the rodent homologue of EAAT2. Lately, we found a highly interesting epigenetic component that influences the basal activity of the human EAAT2 promoter. We found the promoter imbedded in a classical CpG island that is subject to aberrant hypermethylation in EAAT2 negative astrocytic cell lines. Importantly, the transcription of the EAAT2-gene in glioblastoma cells responded to drugs acting on enzymes regulating the epigenetic status (cf. Fig. 1). Therefore, we hope that drugs remodelling epigenetic marks on the DNA might help to pave novel pathways that allow the EAAT2 gene to be transcribed in a more efficient manner.

Research groups involved:

RG Theo Rein: Jürgen Zschocke, Nicole Zimmermann, Tatjana Perisic

RG Jan Deussing: Peter Weber

Publications:

Zschocke J, Allritz C, Engele J, and Rein T. (2007) DNA methylation dependent silencing of the human glutamate transporter EAAT2 gene in glial cells. Glia. 55:663-74