Elsevier

Neuropharmacology

Volume 60, Issues 7–8, June 2011, Pages 1007-1016
Neuropharmacology

Review
Epigenetic GABAergic targets in schizophrenia and bipolar disorder

https://doi.org/10.1016/j.neuropharm.2010.10.021Get rights and content

Abstract

It is becoming increasingly clear that a dysfunction of the GABAergic/glutamatergic network in telencephalic brain structures may be the pathogenetic mechanism underlying psychotic symptoms in schizophrenia (SZ) and bipolar (BP) disorder patients. Data obtained in Costa’s laboratory (1996–2009) suggest that this dysfunction may be mediated primarily by a downregulation in the expression of GABAergic genes (e.g., glutamic acid decarboxylase67 [GAD67] and reelin) associated with DNA methyltransferase (DNMT)-dependent hypermethylation of their promoters.

A pharmacological strategy to reduce the hypermethylation of GABAergic promoters is to administer drugs, such as the histone deacetylase (HDAC) inhibitor valproate (VPA), that induce DNA-demethylation when administered at doses that facilitate chromatin remodeling.

The benefits elicited by combining VPA with antipsychotics in the treatment of BP disorder suggest that an investigation of the epigenetic interaction of these drugs is warranted.

Our studies in mice suggest that when associated with VPA, clinically relevant doses of clozapine elicit a synergistic potentiation of VPA-induced GABAergic promoter demethylation. Olanzapine and quetiapine (two clozapine congeners) also facilitate chromatin remodeling but at doses higher than used clinically, whereas haloperidol and risperidone are inactive. Hence, the synergistic potentiation of VPA’s action on chromatin remodeling by clozapine appears to be a unique property of the dibenzepines and is independent of their action on catecholamine or serotonin receptors.

By activating DNA-demethylation, the association of clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors may be considered a promising treatment strategy for normalizing GABAergic promoter hypermethylation and the GABAergic gene expression downregulation detected in the postmortem brain of SZ and BP disorder patients.

This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’.

Highlights

► Epigenetic mechanisms mediate GABAergic dysfunction in schizophrenia (SZ) and bipolar disorder (BP) patients. ► DNA-methyltransferase (DNMT) is increased in brain of SZ and BP patients. ► An epigenetic strategy to treat SZ and BP is to reduce hypermethylation of GABAergic promoters with valproate and clozapine.

Introduction

This review summarizes our present understanding of the topic of neuroepigenetics in major psychotic disorders. To elucidate the molecular mechanisms whereby nurture (biological or environmental epigenetic factors) and nature (genetic factors) interact to cause major psychiatric disorders such as schizophrenia (SZ) and bipolar (BP) disorder was at the center of Dr. Costa’s mission for the last 15 years of his research at the Psychiatric Institute at the University of Illinois at Chicago (Costa et al., 2002).

Existing drugs used to treat major psychiatric disorders have limited efficacy and substantial side effects. Hence, the challenge for Dr. Costa and his colleagues has been to find new ways to prevent and treat psychiatric disorders with pharmacological agents that fail to have major unwanted side effects.

Section snippets

The challenge to identify the core pathophysiological mechanisms underlying schizophrenia (SZ) and bipolar (BP) disorder that are targeted by antipsychotics

Unfortunately, there are few new leads for future drug development for the treatment of major psychiatric disorders (Miller, 2010a). A fundamental barrier to the identification of more efficacious, less toxic, and faster acting drugs than those presently available to treat BP disorder and SZ is the incomplete understanding of the etiopathogenetic mechanisms underlying the symptomatology of these diseases.

Population, family, and twin studies indicate that SZ and BP disorders are highly heritable

The reciprocal interaction between GABAergic interneurons and glutamatergic pyramidal principal neurons is altered in the cortex or hippocampus of SZ or BP disorder patients

When the postmortem brain of SZ and BP disorder patients is compared to that of non-psychiatric subjects, GABAergic neuropathology is detected in the hippocampus and cortex (Akbarian et al., 1995, Benes et al., 1992, Benes and Beretta, 2001, Fatemi et al., 2000, Guidotti et al., 2000, Guidotti et al., 2005, Impagnatiello et al., 1998, Lewis et al., 2005, Veldic et al., 2007). The GABAergic neuropathology found in the brain of SZ and BP disorder patients is characterized by a decrease in the

Is an altered epigenetic regulation of gene expression the molecular mechanism mediating the GABAergic and glutamatergic dysfunction in SZ and BP disorder?

In SZ and BP disorder patients, the downregulation of GAD67, reelin, and other genes expressed in GABAergic neurons could be a sign of a genetic abnormality. Although a highly conserved single nucleotide polymorphism (SNP) has been identified in the vicinity of the regulatory region of GAD67 (Straub et al., 2007) and of the reelin gene (Shifman et al., 2008, Wedenoja et al., 2008), it is possible that these polymorphisms are associated with an increased risk of psychotic symptoms in a small

DNA promoter methylation patterns in neurons constitute a dynamic process

It was thought that in neurons, DNA-methylation patterns were established during development and remained stable thereafter (Razin and Shemer, 1995). However, there is increasing evidence supporting the concept that in adult neurons, methylation patterns of specific cytosine/guanine (CpG) dinucleotide-rich promoters change rapidly. Thus, throughout life, DNA-methylation provides a platform on which the environment can sculpt the genome and affect neuronal phenotype profiles without altering

Valproate (VPA) and other histone deacetylase (HDAC) inhibitors promote chromatin remodeling, induce DNA-demethylation, and regulate cognitive function

The dynamic nature of the epigenome means that, unlike pathogenic DNA sequence mutations, epigenetic disruptions are potentially reversible and thus a realistic target for pharmacological intervention.

In psychiatry, the use of VPA as a drug that enhances GABAergic transmission is based on the observation that protracted VPA treatment in rodents induces an increase of GAD67 expression (Fig. 3) (see also Loscher, 1999, Tremolizzo et al., 2002). Recent studies from our group and others suggest

Epigenetic processes can be a target of antipsychotic drug action

Recent work has demonstrated that methylation of a promoter CpG island located ∼30 kb upstream of the gene encoding mitogen-activated protein kinase I (MAPK1) is significantly correlated with lifetime antipsychotic use in postmortem PFC samples, with greater lifetime antipsychotic use associated with lower levels of DNA-methylation (Mill et al., 2008). This finding is interesting given the involvement of MAPK1 signaling pathways in mediating intraneuronal signaling and the observation that

Effect of VPA and clozapine on DNA-demethylation

Important for the translational implications, the DNA-demethylating actions of clozapine, olanzapine and quetiapine were synergistically potentiated by the co-administration of a threshold inhibitory dose of VPA (Fig. 4, Table 4, Dong et al., 2008). Furthermore as shown in Table 5, the administration of clozapine (5 mg/kg s.c./three days/twice a day) in conjunction with VPA (70 mg/kg s.c./three days/twice a day) reverses the downregulation of GAD67 expression induced in mice by seven days of

Concluding remarks

Recent breakthroughs in the study of aberrant molecular mechanisms operative in SZ and BP disorder point to a downregulation in the expression of several genes in GABAergic interneurons, most likely caused by gene promoter hypermethylation mediated by overexpression of DNMT in these cells (Costa et al., 2007).

The epigenetic downregulation of telencephalic GABAergic function may be responsible for disinhibiting pyramidal neurons that in turn could provide an excitatory input to dopamine cells in

Acknowledgements

This research was partially supported by NIH grants MH071667 to E. Costa and by MH070855 to A. Guidotti.

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