UMMS Affiliation

Information Services, Academic Computing Services; Department of Cell Biology; Department of Psychiatry

Date

10-19-2007

Document Type

Article

Subjects

Adult; Animals; Cells, Cultured; Child; *DNA Methylation; Female; Glutamate Decarboxylase; Histones; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Myeloid-Lymphoid Leukemia Protein; Prefrontal Cortex; Promoter Regions (Genetics); Rats; Schizophrenia; gamma-Aminobutyric Acid

Disciplines

Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology | Psychiatry

Abstract

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.

Rights and Permissions

Citation: J Neurosci. 2007 Oct 17;27(42):11254-62. Link to article on publisher's site

Comments

Co-author Hsien-Sung Huang is a student in the Neuroscience program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

Related Resources

Link to article in PubMed

PubMed ID

17942719

 
 

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