GABAergic promoter hypermethylation as a model to study the neurochemistry of schizophrenia vulnerability

Abstract

The neuronal GABAergic mechanisms that mediate the symptomatic beneficial effects elicited by a combination of antipsychotics with valproate (a histone deacetylase inhibitor) in the treatment of psychosis (expressed by schizophrenia or bipolar disorder patients) are unknown. This prompted us to investigate whether the beneficial action of this combination results from a modification of histone tail covalent esterification or is secondary to specific chromatin remodeling. The results suggest that clozapine, or sulpiride associated with valproate, by increasing DNA demethylation with an unknown mechanism, causes a chromatin remodeling that brings about a beneficial change in the epigenetic GABAergic dysfunction typical of schizophrenia and bipolar disorder patients.

Keywords::

• antipsychotic
• chromatin remodeling
• DNA demethylase
• DNA methyltransferase inhibitor
• GABAergic neurotransmission
• GAD₆₇
• histone deacetylase inhibitor
• psychosis
• reelin
• valproate

Financial & competing interests disclosure

A Guidotti has funding support (NIMH4RO1MH70855). E Costa has funding support (NIMH2RO1MH71667). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.