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The Journal of Neuroscience, October 17, 2007, 27(42):11254-11262; doi:10.1523/JNEUROSCI.3272-07.2007

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Neurobiology of Disease
Prefrontal Dysfunction in Schizophrenia Involves Mixed-Lineage Leukemia 1-Regulated Histone Methylation at GABAergic Gene Promoters

Hsien-Sung Huang,^1,2 Anouch Matevossian,¹ Catheryne Whittle,¹ Se Young Kim,⁴ Armin Schumacher,⁴ Stephen P. Baker,³ and Schahram Akbarian¹

¹Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, ²Graduate School of Biomedical Sciences, and ³Bioinformatics Unit, University of Massachusetts Medical School, Worcester, Massachusetts 01604, and ⁴Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to Dr. Schahram Akbarian, University of Massachusetts Medical School, Brudnick Neuropsychiatric Research Institute, 303 Belmont Street, Worcester, MA 01604. Email: schahram.akbarian{at}umassmed.edu

Alterations in GABAergic mRNA expression play a key role for prefrontal dysfunction in schizophrenia and other neurodevelopmental disease. Here, we show that histone H3-lysine 4 methylation, a chromatin mark associated with the transcriptional process, progressively increased at GAD1 and other GABAergic gene promoters (GAD2, NPY, SST) in human prefrontal cortex (PFC) from prenatal to peripubertal ages and throughout adulthood. Alterations in schizophrenia included decreased GAD1 expression and H3K4-trimethylation, predominantly in females and in conjunction with a risk haplotype at the 5' end of GAD1. Heterozygosity for a truncated, lacZ knock-in allele of mixed-lineage leukemia 1 (Mll1), a histone methyltransferase expressed in GABAergic and other cortical neurons, resulted in decreased H3K4 methylation at GABAergic gene promoters. In contrast, Gad1 H3K4 (tri)methylation and Mll1 occupancy was increased in cerebral cortex of mice after treatment with the atypical antipsychotic, clozapine. These effects were not mimicked by haloperidol or genetic ablation of dopamine D₂ and D₃ receptors, suggesting that blockade of D₂-like signaling is not sufficient for clozapine-induced histone methylation. Therefore, chromatin remodeling mechanisms at GABAergic gene promoters, including MLL1-mediated histone methylation, operate throughout an extended period of normal human PFC development and play a role in the neurobiology of schizophrenia.

Key words: nucleosome; epigenetic; single-nucleotide polymorphism; glutamic acid decarboxylase; interneuron; psychosis; cortical development; aging

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Received July 18, 2007; revised Aug. 26, 2007; accepted Sept. 3, 2007.

Correspondence should be addressed to Dr. Schahram Akbarian, University of Massachusetts Medical School, Brudnick Neuropsychiatric Research Institute, 303 Belmont Street, Worcester, MA 01604. Email: schahram.akbarian{at}umassmed.edu

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