Trends in Pharmacological Sciences
OpinionCharacterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling
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-HT2A) 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 GAD67, 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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