Valproic acid and chromatin remodeling in schizophrenia and bipolar disorder: Preliminary results from a clinical population

Abstract

Levels of acetylated Histone 3 and 4 proteins are strongly predictive of a chromatin structure that is conducive to gene expression. In cell and animal studies, valproic acid is a potent inhibitor of histone deactylating enzymes, and consequently results in increased levels of acetylated Histone 3 (acH3) and acetylated Histone 4 proteins (acH4). To examine this effect in a clinical setting, 14 schizophrenic and bipolar patients were treated with valproic acid (Depakote ER®), either as monotherapy or in combination with antipsychotics, over a period of 4 weeks. AcH3 and acH4 levels from lymphocyte nuclear protein extracts were measured by Western Blot. Treatment with Depakote ER resulted in a significant increase of acH3 and a trend-level increase of acH4. Levels of valproic acid were positively and significantly correlated with percent increase in acH3 but not acH4. Schizophrenia patients were significantly less likely to increase their acH3 and acH4 levels after 4 weeks on Depakote ER. The authors consider these results in the context of future application of HDAC inhibitors to the treatment of psychiatric disorders.

Introduction

The genome is packaged into regions that are accessible (euchromatin) and those that are sequestered from activity-inducing proteins (heterochromatin) (Struhl, 1999). Chromatin, especially that located in the vicinity of regulatory DNA sequences, is a highly interactive platform for promoter regulation, and its regulatory properties are based on physical and chemical adaptations of the cytosine nucleotide (part of the DNA sequence), and amino acid residues in the histone tail (Berger, 2002, Geiman and Robertson, 2002). The acetylation of specific amino acid residues, such as Lysine at position 9 (H3^aceK9) on the amino tail of H3 histones or Lysine at position 8 (H4^aceK8) on the amino tail of H4 is associated with a relaxed or transcriptionally facilitative chromatin structure (Kurdistani et al., 2004). Removal of the acetyl group by the histone deacetylase (HDAC) family of enzymes results in a closed or ‘silent’ chromatin structure. Valproic acid has only recently been discovered to be an effective inhibitor of HDACs in concentrations that are commensurate with widely used clinical levels (Phiel et al., 2001, Gottlicher et al., 2001, Tremolizzo et al., 2005). Associated with this chromatin-relaxing property, valproic acid has demonstrable effects in enhancing the gene expression of candidate molecules relevant to the pathophysiology of schizophrenia such as reelin (Chen et al., 2002, Noh et al., 2005). Reelin is a particularly representative example of an epigenetically controlled schizophrenia candidate gene whose expression is regulated in part by the level of DNA methylation and chromatin structure in the vicinity of its promoter (Chen et al., 2002) and is reduced in the postmortem brains of schizophrenia patients (Guidotti et al., 2000, Torrey et al., 2005). Indeed, aberrant methylation of the reelin gene promoter (Grayson et al., 2005, Abdolmaleky et al., 2005), as well as variant histone protein modification (Akbarian et al., 2005), is now documented by several independent groups in the postmortem brain of schizophrenia patients.

This study was designed to document the characteristics of the chromatin remodeling response in psychiatric patients treated with an HDAC inhibitor such as Depakote ER, and to compare this response between schizophrenia and bipolar patients (Sharma, 2005a, Sharma et al., 2005b).