REELIN and schizophrenia: a disease at the interface of the genome and the epigenome.
The downregulation of the Reelin gene (RELN) that occurs in schizophrenic brains, which are characterized by pyramidal neurons with shortened dendrites and by reduced expression densities of dendritic spines, may well result from hypermethylation of the RELN promoter. In the adult mammalian brain, gamma-aminoburytic acid-secreting (GABAergic) interneurons release RELN into the extracellular matrix, where it binds with high affinity to the integrin receptors present at dendritic spine postsynaptic densities and likely plays a role, elaborated in this article, in synaptic plasticity. In heterozygous reeler mice, which are haploinsufficient in RELN, inhibitors of histone deacetylase increase DNA demethylase activity and restore RELN expression. Such inhibitors could thus be of therapeutic value in mitigating vulnerability to schizophrenia among high-risk individuals.
Psychiatric Institute Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA. costa@psych.uic.edu
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Costa
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Chen
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Davis
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Noh
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Tremolizzo
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Veldic
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Grayson
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Guidotti
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000096:biosynthesis* / Q000502:physiology; D019175:DNA Methylation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000502:physiology; D000091042:Reelin Protein; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000502:physiology
D015816:Cell Adhesion Molecules, Neuronal; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D056572:Histone Deacetylase Inhibitors; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases