P.347 Role of HDAC5 and SIRT2 in depression and clinical efficacy of antidepressants

ABSTRACT

Background: Epigenetic mechanisms can play a key role in the pathogenesis of depression and its treatment. Specifically, changes in histone acetylation mediated by HDAC5 and SIRT2 can regulate the transcription of genes related to different functions such as brain plasticity [1]. Previous studies in peripheral blood mononuclear cells (PBMCs) [2] and prefrontal cortex (PFC) in patients and murine models show that depressive phenotype is associated with an increase of HDAC5 and SIRT2. On the other hand, Sirt2 and Hdac5 RNAm are decreased by chronic antidepressant treatment [3]. Moreover, drugs that work by inducing an increase in norepinephrine in the synapse, are able to phosphorylate HDAC5 causing a migration from nucleus to cytoplasm and therefore, the enzyme would lose its deacetylase function [3,4,5]. Objectives: To evaluate if HDAC5 and SIRT2 in PBMCs could be peripheral markers for depressive state or antidepressant treatment. More specifically, we would like to discover if major depression illness has a determinant effect in the nucleocytoplasmic distribution of HDAC5 and SIRT2, and also if these features can influence in the phosphorylation capacity of HDAC5 by duloxetine and some adrenergic and serotonergic agonists. Sex and age factors will be also studied. At transcriptional level, we would like to know how depressive state and antidepressant therapy could regulate the expression of genes that are related to HDAC5 and SIRT2 function, as those related to neuroplasticity, angiogenesis and inflammation (Bdnf, Vegf, eNOS, KLF-2, FOXP3, CTLA-3, PD-1). Sex and age factors will be also studied. Methods: Depressive patients (Montgomery-Asberg>=20) and healthy volunteers (MAsberg<7) were recruited by psychiatrists from different hospitals and health care centres. 20 ml of blood were extracted in order to obtain PBMCs (classic, intermediate and non-classic monocytes and T-cells) using Ficoll-paque followed by FACs. Isolated cells were used for culture and immunofluorescence and for RNAm extraction for PCR. Nucleocytoplasmic distribution of SIRT2 and HDAC5 was measured by confocal microscopy, and a ratio of mean intensities between cytoplasm and nucleus was calculated. However, the effect of in vitro treatments were analysed by fluorescence microscopy, looking at the intensity of HDAC5 phosphorylation. Results: Depressed patients showed a lower ratio (cytoplasm/nucleus) for SIRT2 in classic and intermediate monocytes as well as in T-cells, compared to healthy volunteers. In addition, looking at the HDAC5 phosphorylation in monocytes and T-cell cultures induced by the antidepressant duloxetine in vitro, it was observed that depressed patients showed a lower response compared to healthy volunteers. Regarding age and sex factors, female healthy volunteers between 40 and 50 years old showed a lower ratio (cytoplasm/nucleus) for HDAC5 compared to the young, between 20 and 30 years old, and old (between 65 and 80 years old) healthy volunteers. Gene expression studies are on course and hopefully they will be finished after Covid19 crisis and before the congress. Conclusion. It seems that HDAC5 and SIRT2 in monocytes and T-cells could be suitable peripheral biomarkers for depressive state or for evaluating treatment efficacy. These results might also suggest that age and sex are determinant factors. No conflict of interest