Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling

doi:10.1016/j.tips.2008.10.010

Trends in Pharmacological Sciences

Volume 30, Issue 2, February 2009, Pages 55-60

https://doi.org/10.1016/j.tips.2008.10.010 Get rights and content

Recent advances in schizophrenia (SZ) research indicate that the telencephalic γ-aminobutyric acid (GABA)ergic neurotransmission deficit associated with this psychiatric disorder probably is mediated by the hypermethylation of the glutamic acid decarboxylase 67 (GAD₆₇), reelin and other GABAergic promoters. A pharmacological strategy to reduce the hypermethylation of GABAergic promoters is to induce a DNA-cytosine demethylation by altering the chromatin remodeling with valproate (VPA). When co-administered with VPA, the clinical efficacy of atypical antipsychotics is enhanced. This prompted us to investigate whether this increase in drug efficacy is related to a modification of GABAergic-promoter methylation via chromatin remodeling. Our previous and present results strongly indicate that VPA facilitates chromatin remodeling when it is associated with clozapine or sulpiride but not with haloperidol or olanzapine. This remodeling might contribute to reelin- and GAD₆₇-promoter demethylation and might reverse the GABAergic-gene-expression downregulation associated with SZ morbidity.

Introduction

Recent advances in schizophrenia (SZ) research indicate that a deficit of brain γ-aminobutyric acid (GABA)ergic function detected in these patients is related to the downregulation of several GABAergic genes, including glutamic acid decarboxylase 67 (GAD₆₇) and reelin. This downregulation could be a pathogenetic mechanism underlying the complex symptomatology of SZ 1, 2, 3, 4. This includes positive psychotic (e.g. hallucination, delusion and thought disorders), negative (i.e. anhedonia) and cognitive (e.g. attention, executive and memory dysfunctions) symptoms.

In the prefrontal cortex (PFC) and basal ganglia GABAergic neurons of SZ patients, an increase of DNA methyltransferase 1 (the enzyme that transfers a methyl group from S-adenosylmethionine to carbon 5 of the cytosine pyrimidine ring embedded in cytosine-phospho-guanine [CpG] islands containing promoters) hypermethylates selected GABAergic promoters [5]. This increase is probably among the leading causes of GAD₆₇, reelin and other gene-expression downregulation. Hence, a pharmacological intervention that normalizes GABAergic neurotransmission is emerging as novel target in the strategy to treat SZ morbidity 2, 3.

The antipsychotic medications presently used were not designed to target GABAergic transmission. In fact, the current antipsychotics are meant to target monoamine neurotransmitter receptors such as dopamine (D₂) receptors (targeted by typical antipsychotics including chlorpromazine, haloperidol and perphenazine), serotonin (5-HT_2A) or other monoamine receptors (targeted by atypical antipsychotics including clozapine [CLZ], olanzapine [OLZ], risperidone and quetiapine) 6, 7. Indeed, a majority of the available antipsychotics, with the exception of CLZ and sulpiride (SULP), failed to ameliorate the negative and cognitive symptoms associated with SZ 6, 7, 8. This indicates that a monoamine receptor antagonism might not fully account for the larger spectrum of the clinical beneficial action of CLZ or SULP and for the unique efficacy of CLZ in patients resistant to other antipsychotic treatments.

The discovery of antipsychotics with improved clinical efficacy has been hampered by our incomplete understanding of the cellular mechanisms underlying SZ morbidity.

For example, the use of valproate (VPA) as a drug that facilitates the action of CLZ 9, 10 is based on empirical observations and not on a complete understanding of the underlying molecular and cellular pathologies. Here, we hypothesize that when CLZ or SULP are co-administered with VPA (a histone deacetylase inhibitor [11]) these antipsychotics might facilitate an open state conformation of chromatin (Box 1), which reduces the epigenetic GABAergic neuron modifications that mediate psychotic symptoms.

Section snippets

The role of GAD₆₇ and reelin in SZ

The reduced expression of GAD₆₇, reelin and other genes expressed in GABAergic interneurons is among the most consistent molecular alteration underlying the frontal cortex circuit dysfunction believed to be operative in SZ 1, 2, 3, 4, 5. GAD₆₇ is the most important enzyme regulating GABA synthesis because it catalyzes ∼70% of brain GABA turnover [12]. Hence, a large reduction (60% or more) of GAD₆₇ expression in specific GABAergic interneurons of the PFC and hippocampus of SZ patients might

Role of epigenetics in SZ vulnerability

In SZ, the downregulation of GAD_67, reelin and other genes expressed in GABAergic neurons could reflect genetic abnormalities. Although a highly conserved single nucleotide polymorphism (SNP) has been identified in the vicinity of the regulatory region of GAD₆₇ [19] and reelin genes 20, 21, these polymorphisms increase risk of psychotic symptoms in sporadic familial cases 22, 23.

Several lines of evidence 5, 24, 25, 26 indicate that an altered epigenetic mechanism could be responsible for a

nAChR agonists target DNMT1

An exciting development in the regulation of DNMT1 expression in GABAergic neurons is that the administration of nicotine and other synthetic nAChR agonists can improve both cognitive and negative symptoms in SZ patients 31, 32. It is known that a large number of SZ patients abuse tobacco, and because the active component inhaled in cigarette smoking is nicotine the high level of smoking in SZ patients could be linked to self medication in an attempt to correct or minimize the cholinergic

Histone deacetylase inhibitors acting on the histone code promote DNA demethylation in GABAergic neurons

There is now increasing evidence that, in adult neurons, DNA methylation patterns might change rapidly under the influence of environmental factors, toxins or drugs that modulate chromatin remodeling 30, 33, 34.

The elementary unit of chromatin is the nucleosome that is formed by an octamer of histone proteins [35]. The N-terminal tails of lysines in these histones might be extensively modified by acetylation or methylation. It has been proposed that the pattern of histone N-terminal tail

Modulation of the histone code by antipsychotics

The symptomatic benefits elicited by a combination of VPA with antipsychotics in the treatment of SZ 9, 10 prompted us to study whether this drug combination could mediate changes in specific chromatin remodeling processes, including histone-tail acetylation and demethylation of hypermethylated GABAergic promoters (i.e. modulating reelin and GAD₆₇ expression).

As proof of concept, experiments were carried out with various antipsychotics including haloperidol (HAL; a selective D₂-receptor

Conclusions

The findings discussed here indicate that the overexpression of DNMT1 in telencephalic GABAergic neurons of SZ patients might be responsible for an epigenetic hypermethylation of specific GABAergic gene promoters, including those regulating GAD₆₇ and reelin 5, 25, 28, 29. The transcriptional downregulation of both genes is likely to lead to a downregulation of GABAergic transmission, resulting in a disinhibition of pyramidal neurons that presumably have an important role in the pathogenetic

Acknowledgements

This work was supported, in part, by National Institute of Mental Health (www.nimh.nih.gov) grants MH071667 (to E.C.), MH070855 (to A.G.) and MH62682 (D.R.G.).

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Individuals with psychosis, including schizophrenia (SZ) and bipolar disorder patients (BP) with psychosis (BP+), express a complex symptomatology characterized by core symptoms that include positive and negative symptoms, as well as cognitive impairment. Autism spectrum disorders (ASD) are characterized by impaired social interactions, altered verbal and non-verbal communications, and repetitive or stereotyped behaviors. Although each disorder has a unique morbidity, age of onset, temporal progression, and responsiveness to pharmacological therapy, there are some shared features with respect to symptomatology that suggest common or overlapping endophenotypes. Postmortem studies of human SZ and BP+ brains indicate that there are considerable alterations in the transcriptome of a variety of cortical and limbic structures which, in turn, likely reflect widespread changes in the epigenome. mRNA profiling studies show expression levels that are both up- and/or downregulated in inhibitory GABAergic interneurons, excitatory (glutamatergic) pyramidal neurons, and glia at distinct stages of adolescent maturation and in the adult compared with non-psychiatric subjects (NPS). Alterations in the transcriptome and the epigenome have also been demonstrated in multiple types of neurons and brain regions in ASD, as well as in psychosis. Major depressive disorder (MDD) and suicide completers may also exhibit distinct and overlapping alterations in the epigenome. Many of the symptomatic phenotypes associated with these complex psychiatric disorders are likely the consequence of early-life stressors that occur during prenatal or early-life neurodevelopment. The establishment and maintenance of DNA methylation are essential during central nervous system maturation and neuronal differentiation. We propose that these DNA modifications represent interconvertible epigenetic states that are context dependent and likely associated with early developmental stress. Whereas CpG methylation is linked with transcriptional downregulation, the role of hydroxymethylation in transcriptional regulation is less clear although it is most often associated with transcriptional activation and RNA splice site selection. Studies also show that CpG binding by methyl-CpG-binding domain proteins acts to both facilitate and antagonize repressed chromatin. DNA-modifying proteins, such as DNMT1 and TET1, also bind CpGs independent of their catalytic function. In addition, both DNMT1 and MeCP2 are more abundant in GABAergic cortical neurons and hippocampal neurons, suggesting the possibility that inhibitory interneurons may differ in how they regulate gene expression as compared with excitatory neurons. Recent experimental observations raise the possibility that neuron-specific targets may be differentially exploited for pharmacological intervention in treating selective endophenotypes associated with psychiatric disorders. There is also widespread interest in understanding whether genome-wide methylation (methylomic) biomarkers present in blood might be useful in predicting BP+, SZ, BP, MDD, ASD, suicide, and responsiveness to specific psychiatric medications.
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Epigenetic regulatory mechanisms are influenced by many pharmaceutical compounds including psychotropic drugs. In this chapter, the current state of knowledge on how several traditional psychotropic drugs alter the epigenome is reviewed. Sodium valproate is the most obvious example, because it is a known HDAC inhibitor. Antidepressants, including selective serotonin reuptake inhibitors (fluoxetine, citalopram), as well as tricyclic antidepressants (imipramine, amitriptiline) and monoamine oxidase inhibitors, influence the epigenome. Antipsychotics (clozapine, haloperidol) and to a lesser extent lithium influence the epigenome, and for these compounds there is evidence that part of the epigenetic effects are mediated via microRNAs. The effects of currently used psychotropic drugs on epigenetic mechanisms of gene expression and how these effects may contribute to the therapeutic benefits of these drugs are discussed. The role of epigenetics in psychopharmacological treatment response is just starting to become clear, but what we do know suggests that there is vast potential for further development of epigenetic drugs.
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Almost four decades ago an altered chromatin structure was described in the neutrophils of patients with SCZ. More recent studies reported an increase in the level of histone 3-(methyl) arginine 17 associated with decreased expression of several metabolic genes in the prefrontal cortex of SCZ patients. Transcriptome analyses also revealed aberrant expression of histone deacetylase3 (HDAC3) in the temporal cortex, and dysregulation of many histone- related genes in the blood of SCZ patients. While there are reports on increased expression of HDAC1 in the frontal cortex and hippocampus of SCZ patients and an inverse correlation between the expression of GAD67 (GAD1) and the expression of HDAC1, HDAC3 and HDAC4, in studies using transgenic mice expressing HDAC1 in the prefrontal cortex uncovered deficit in working memory and down-regulation of several genes linked to SCZ. Consistent with these observations, valproate was shown to increase H3 acetylation in lymphocytes of SCZ patients as well as H3K9, K14 acetylation of the GAD67 promoter region. Additionally, clozapine and sulpiride were shown to facilitate valproate-induced chromatin remodeling. Furthermore, in large-scale GWAS studies genes involved in histone methylation processing exhibited the strongest association with major psychiatric diseases, including SCZ. In other studies, an increased baseline level of H3K9^me2 (a repressive chromatin mark) was also observed in lymphocytes and in postmortem brain tissues of SCZ patients, coupled with a younger age of disease onset. While in general, there is an age-dependent increase in H3K4^me at the GAD1 promoter, a decrease of GAD1 promoter H3K4^me associated with reduced GAD1 expression has been reported in the prefrontal cortex of SCZ patients that was due to MLL1 histone methyltransferase dysfunction in neurons. Interestingly, higher order chromatin structures that delineate chromosomal looping and modulate physical contact of promoter regions to cis acting enhancers/silencers are also altered at the GAD1 promoter region associated with GAD1 expression changes in the frontal cortex of SCZ patients. More recent studies also report aberrant ubiquitination, ufmylation, SUMOylation, and NEDD8ylation in the superior temporal gyrus of SCZ patients.
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Schizophrenia (SZ) is associated with cognitive impairment that contributes to disability, but the cognitive dysfunction is relatively refractory to pharmacologic intervention. Though Valproate augmentation is reported to improve psychopathology among patients with SZ, its effects on cognitive functions have not been investigated systematically.
Using a randomized double blind placebo controlled design, the effects of Valproate or placebo as adjuncts to risperidone (RISP) treatment were evaluated among patients with early course SZ (N = 109). Domains of cognitive function, estimated using the Arabic version of the Penn Computerized Neurocognitive Battery, were the prime outcomes. Clinical severity and social function were secondary outcomes. We also explored the effects of valproate treatment on serological responses to Toxoplama Gondii (TOXO), a putative risk factor for cognitive dysfunction in SZ.
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Trends in Pharmacological Sciences

OpinionCharacterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling

Introduction

Section snippets

The role of GAD67 and reelin in SZ

Role of epigenetics in SZ vulnerability

nAChR agonists target DNMT1

Histone deacetylase inhibitors acting on the histone code promote DNA demethylation in GABAergic neurons

Modulation of the histone code by antipsychotics

Conclusions

Acknowledgements

Neuropsychopharmacology

Trends Pharmacol. Sci.

Neurobiol. Dis.

Biochim. Biophys. Acta

Neuropsychopharmacology

Am. J. Hum. Genet.

Schizophr. Res.

Biol. Psychiatry

Cell

Trends Neurosci.

Schizophr. Res.

Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics

Arch. Gen. Psychiatry

GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon

Psychopharmacology (Berl.)

Cortical inhibitory neurons and schizophrenia

Nat. Rev. Neurosci.

Reviewing the role of DNA (cytosine-5) methyltransferase overexpression in the cortical GABAergic dysfunction associated with psychosis vulnerability

Epigenetics

The pipeline and future of drug development in schizophrenia

Mol. Psychiatry

Schizophrenia: new pathological insights and therapies

Annu. Rev. Med.

Amisulpride augmentation of clozapine: an open non-randomized study in patients with schizophrenia partially responsive to clozapine

Acta Psychiatr. Scand.

Adjunct divalproex or lithium to clozapine in treatment-resistant schizophrenia

Psychiatr. Q.

Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia

J. Clin. Psychopharmacol.

An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability

Proc. Natl. Acad. Sci. U. S. A.

Opinion
Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling

The role of GAD₆₇ and reelin in SZ