Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

Abstract

Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II-and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamineinduced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine.ketamine | HDAC | depression | hippocampus D epression is a multifaceted illness, characterized by somatic, cognitive, and behavioral changes. All currently available antidepressants primarily act via monoaminergic neurotransmitters, such as serotonin and/or noradrenaline (1). Currently available pharmacotherapies for depression provide some relief for patients, but these agents have significant limitations (1). In this context, new antidepressants with faster onset of action and greater efficacy are needed (2).The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown remarkable consistency in rapidly ameliorating depressive symptoms in major depressive disorder (MDD) (3). Preclinical studies have demonstrated that ketamine produces rapid antidepressant responses (within hours) (4, 5). Ketamine's antidepressant effects in rodents are associated with activation of several signaling systems including the mammalian target of rapamycin complex 1 (mTORC1) (4), brain derived neurotrophic factor (BDNF) and elongation factor 2 (EF2) kinase (5). Despite these remarkable effects, the widespread use of ketamine is limited by potential side effects and abuse. Thus, studies are necessary to further elucidate mechanistic actions of ketamine at cellular and network levels.Recent studies have generated evidence that epigenetic regulation is closely involved in the pathophysiology of depression and in the therapeutic mechanisms of typical antidepressants (6, 7). In addition, reports that sodium butyrate, a histone deacetylase (HDAC) inhibitor, has antidepressant effects indicate that HDAC inhibition is sufficient to produce an antidepressant response (8). HDACs are a family of enzymes capable of repressing gene expression by removing acetyl groups from histones to produce a less accessible chromatin structure (9).Previous studies demonstrate that the...

Ketamine: 50 Years of Modulating the Mind

“…Ketamine acutely increases hippocampal proteins brain-derived neurotrophic factor (BDNF; Garcia et al, 2008; Yang et al, 2013) and mammalian target of rapamycin (mTOR; Yang et al, 2013), which may also help to explain the mechanism for its rapid antidepressant effects. Indeed, investigation into ketamine’s antidepressant effects have led to several reports that ketamine may affect various brain regions through epigenetic mechanisms, such as histone deacetylase modulation (Reus et al, 2013; Choi et al, 2015) and increased BDNF mRNA expression (Duman and Voleti, 2012). …”

A role for activity‐dependent epigenetics in the development and treatment of major depressive disorder

“…52 Interestingly, blocking NMDA activity with the noncompetitive antagonist ketamine, can induce the nuclear export of HDAC5 and may represent a novel, fast-acting treatment for MDD (see below). 53 The coordinated activation and translocation of HATs and HDACs suggests that acetylated histones play a role in regulating activity-dependent neuronal transcription and may provide an interesting avenue of investigation in the etiology of neuropsychiatric illness.…”

Understanding epigenetic architecture of suicide neurobiology: A critical perspective

“…Similarly, dimethylation of H3K9 and H3K27 by imipramine (Wilkinson et al, 2009) was found to be equally effective in upregulating transcription of genes which could potentially be directed towards reversing dysfunctional cognitive system. Despite the controversy related to its recreational use and abuse, ketamine has been used to stabilize the mood with a moderate dose by augmenting epigenetic alteration in neurochemical pathways with its fast mode of antidepressant function (Choi et al, 2015). Recent evidence has shown its effectiveness in moderating the impulsivity associated with suicidal ideation of mood disorder patients (Price et al, 2014; Thakurta et al, 2012).…”

“…An overall reversal of depressive symptom in the same study cohort found to be paralleled with the observed anti-suicidal tendency which indicated a positive role of ketamine in regulating AMPA to NMDA receptor throughput, changes in synaptic connections and enhancing the BDNF signaling (Price et al, 2014). However, a link was still missing to establish the intermediate role of ketamine as epigenetic modulator until a recent report from preclinical study pointed out HDAC5 modulation in hippocampal neurons (Choi et al, 2015). The report helped to understand ketamine’s role in rapidly stimulating histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons with direct involvement of calcium/calmodulin kinase II- and protein kinase D-dependent pathways.…”