The role of HDAC5, SIRT2 and VGLUT1 in antidepressant action

Resumen

Depression is a chronic disorder characterized mainly by depressive mood and anhedonia. The monoaminergic hypothesis has resulted deficient to explain the biological changes that may be caused in the depressive brain. Other hypotheses like alterations in the neuroplasticity, in glutamate transmission, as well as in epigenetics have been proposed. Antidepressant action has been linked to increased synaptic plasticity in which epigenetic mechanisms such as histone posttranslational acetylation could be involved. Interestingly, previous studies in our laboratory have shown that the histone deacetylases HDAC5 and SIRT2 are oppositely regulated by stress and antidepressants in mice prefrontal cortex (PFC). Besides, the neuroblastoma SH-SY5Y line is an in vitro neuronal model reliable to study drug effects with clear advantages over animal models. This study focuses on the possible role of two selected epigenetic targets (histone deacetylase 5, HDAC5, and sirtuin 2, SIRT2) and one glutamate target (vesicular glutamate transporter 1, VGLUT1) in antidepressant action. The first aim was to further explore the role of HDAC5 and SIRT2 in the molecular mechanisms of antidepressants using the in vitro SH-SY5Y cellular model. This study shows that nucleocytoplasmic export of HDAC5 and SIRT2 downregulation mediated by antidepressants could enhance synaptic plasticity markers leading to antidepressant action. The second aim of this study was to evaluate the therapeutic potential of SIRT2 for depression treatment. A course of treatment with the selective SIRT2 inhibitor 33i reversed anhedonia in mice heterozygous for the vesicular glutamate transporter 1 (VGLUT1+/-), considered a genetic model of depression. In parallel, we initiated a study directed to examine the role of the glutamate target VGLUT1 in the long-loop mechanisms of control of 5-HT activity as well as in the modulation of depressive-like behaviors. Using the adeno-associated virus (AAV) technology, VGLUT1 expression was induced in the PFC of VGLUT1+/-. Interestingly, these preliminary studies have evidenced that VGLUT1 expression in the PFC of VGLUT1+/- mice is linked to antidepressant action. Altogether, HDAC5 and SIRT2 as well as the synaptic plasticity marker VGLUT1 could be proposed as pharmacological targets involved in antidepressant action.