Altered epigenetic mechanisms related to GABA synthesis identified in schizophrenic brains
Original article
Huang H-S et al. (2007) Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. J Neurosci 27: 11254–11262 PubMed
Abnormalities in the GABA neurotransmitter system are thought to have a role in the development of schizophrenia. Having investigated the molecular mechanisms that underlie these abnormalities, researchers now describe specific alterations in chromatin markers relating to the regulation of genes coding for GAD1 and other key enzymes involved in GABA synthesis.
Trimethylation and monomethylation of histone H3-lysine 4 (processes involved in chromatin remodeling and transcription initiation) increased progressively with age in the human and the mouse cerebral cortex at the GAD1/Gad1 promoter, as well as at the promoters of other GABAergic gene loci. By comparison, brains from patients with schizophrenia and especially females, showed reduced GAD1 mRNA expression and H3K4 trimethylation. The study also suggested a role for mixed-lineage leukemia 1 (Mll1), a histone methyltransferase expressed in GABAergic and other cortical neurons, because histone methylation was decreased in MLL1 mice. Finally, the antipsychotic drug clozapine increased Gad1 H3K4 (tri)methylation in mice, as well as increasing MLL1 mRNA, suggesting that medications aimed at correcting the described mechanistic flaws could be developed.
This research indicates major differences between normal development and schizophrenia. In the normal brain there is progressive increase in H3K4 methylation at GABAergic gene promoters; however, in some patients with schizophrenia, histone methylation at GABAergic promoters is decreased, but can be increased by treatment with antipsychotic agents such as clozapine.
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Subject areas under which this article appears: Neuropsychiatric disorders | Genetics