Altered gene expression of histone deacetylases in mood disorder patients

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Abstract

Chromatin remodeling such as changes in histone acetylation has been suggested to play an important role in the pathophysiology and treatment of mood disorders. In the present study, we investigated whether the expression of histone deacetylase (HDAC) genes are altered in mood disorder patients. We used quantitative real-time PCR to measure the mRNA levels of 11 HDACs (HDAC1-11) in peripheral white blood cells of major depressive disorder (MDD) and bipolar disorder (BPD) patients during depressive and remissive episodes and in the first-degree relatives of BPD patients. In addition, we investigated the effect of antidepressants and mood stabilizers on the mRNA levels of HDACs using mice. In MDD, the expression of HDAC2 and −5 mRNA was increased in a depressive state, but not in a remissive state, compared to controls. In BPD, the expression of HDAC4 mRNA was increased only in a depressive state, and the expression of HDAC6 and −8 was decreased in both depressive and remissive states compared to controls, whereas the first-degree relatives did not show any significant alteration in expression levels. Animal study showed that the expression of HDAC2 and −5 or HDAC4, −6 and −8 mRNAs in the mouse leukocytes were not affected by chronic treatment with antidepressants or mood stabilizers. Our data suggest that aberrant transcriptional regulation caused by the altered expression of HDACs is associated with the pathophysiology of mood disorders.

Introduction

There is growing evidence demonstrating that aberrant transcriptional regulation is one of the key components of the pathophysiology of many neuropsychiatric disorders, including mood disorders, schizophrenia and drug addiction (Colvis et al., 2005, Tsankova et al., 2007). The altered expression and/or activity of a variety of transcription factors such as cAMP-responsive element binding protein (CREB) and glucocorticoid receptor (GR) have been reported in patients with mood disorder, as well as in stressed animals (Carlezon et al., 2005, de Kloet et al., 2005, Holsboer, 2000, Laifenfeld et al., 2005, Nestler et al., 2002, Webster et al., 2002). In addition, antidepressant treatment and electroconvulsive therapy alter gene expression patterns in the brain (Coyle and Duman, 2003, Manji et al., 1999). Mood disorder patients and chronically stressed humans have also been reported to show altered gene expression in peripheral blood cells (Anitha et al., 2008, Matsubara et al., 2006, Miller et al., 2008, Otsuki et al., 2008).

Chromatin remodeling is suggested to play important roles in many phenomena in the brain, including circadian rhythm (Etchegaray et al., 2003), memory formation (Guan et al., 2002, Korzus et al., 2004, Levenson and Sweatt, 2005), drug addiction (Kumar et al., 2005) and depression (Berton and Nestler, 2006, Newton and Duman, 2006, Tsankova et al., 2006). It has been widely recognized that changes in chromatin structure play a role in the regulation of gene expression attributable to covalent histone modification via acetylation and deacetylation (Grunstein, 1997, Hsieh and Gage, 2005). Histone deacetylases (HDACs) are one of the major enzymes involved in chromatin remodeling (Grunstein, 1997, Hsieh and Gage, 2005). HDACs can remove acetyl groups from lysine/arginine residues in the amino-terminal tails of core histones, thereby allowing histones in the deacetylated state to pack DNA into more condensed chromatin, which prevents access of transcriptional activators to their target sites, resulting in transcriptional repression (Grunstein, 1997, Hsieh and Gage, 2005).

A recent report has indicated that hippocampal HDAC5 mRNA is downregulated after chronic treatment with the tricyclic antidepressant imipramine, and viral-mediated HDAC5 overexpression in the hippocampus blocks the effect of imipramine on depression-like behaviors in mice (Tsankova et al., 2006). Another report suggested that sodium butyrate, an HDAC inhibitor, has antidepressant-like effects on behavioral despair in mice (Schroeder et al., 2007). Valproate, a therapeutic agent for bipolar disorder, is a direct inhibitor of HDAC (Gottlicher et al., 2001, Phiel et al., 2001). These observations suggest that HDACs are involved in the pathophysiology of mood disorders and the action of antidepressants and mood stabilizers. However, there is very little understanding of the role of HDACs in mood disorders.

In this study, we aimed to determine whether there are alterations in the expression of multiple HDAC mRNA in peripheral white blood cells of mood disorder patients. Also, to examine whether the altered mRNA expression of HDACs is state- or trait-dependent, mood disorder patients in remission and their first-degree relatives were also assessed. We also examined the mRNA levels of HDACs in mice receiving antidepressants or mood stabilizers to investigate the effects of these drugs on the expression of HDACs.

Section snippets

Subjects

Major depressive and bipolar disorder patients were diagnosed according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (American Psychiatric Association, 1994). These included both outpatients and inpatients of the Division of Neuropsychiatry of the Yamaguchi University Hospital. The extent of the depressive state was assessed by a 21-item “Hamilton Depression Rating Scale” (HDRS). Subjects were classified as under a current depressive state when

mRNA levels of HDACs in mood disorder patients

Table 1 shows the demographic and clinical characteristics of the subjects. The majority of the patients were on medication. The mean ages were not significantly different among major depressive disorder patients, bipolar depressive patients and healthy control subjects [F(4,127) = 1.164, p = 0.330]. Regarding the gender distribution, bipolar disorder patients showed a significantly larger ratio of females to males (χ2 = 16.20, p < 0.001). In multivariable analyses (n = 104), the mRNA levels of all the

Discussion

In this study, we found different alteration pattern of HDACs mRNA expression levels in peripheral blood cells of major depressive disorder and bipolar disorder patients. Our data clearly suggest that the increased expression of HDAC2 and −5 mRNA is state-dependent in major depressive disorder patients. In bipolar disorder patients, the increased expression of HDAC4 mRNA is state-dependent, whereas the reduction of HDAC6 and −8 mRNA expression is trait-dependent.

Although we found the altered

Conflict of interest

There are no conflicts of interest including any financial, personal, or other relationships with people for any of the coauthors related to the work described in the article.

Contributors

T. Hobara, S. Uchida and Y. Watanabe designated the research. T. Hobara, S. Uchida, K. Otsuki, T. Matsubara, H. Funato, K. Matsuo and M. Suetsugi performed the experiments. The manuscript was written by T. Hobara, S. Uchida and Y. Watanabe. All authors discussed results and commented on the manuscript.

Funding source

This study was supported in part by a Grant-in-Aid for Scientific Research from Japanese Ministry of Education, Culture, Sports, Science and Technology and a grant for Research on Psychiatric and Neurological Diseases and Mental Health from Japanese Ministry of Health, Labor and Welfare.

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    These authors contributed equally to this work.

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