Ischemic insults promote epigenetic reprogramming of μ opioid receptor expression in hippocampal neurons

Luigi Formisano, Kyung Min Noh, Takahiro Miyawaki, Toshihiro Mashiko, Michael V.L. Bennett, R. Suzanne Zukin

106 Scopus citations

Abstract

Transient global ischemia is a neuronal insult that induces delayed, selective death of hippocampal CA1 pyramidal neurons. A mechanism underlying ischemia-induced cell death is activation of the gene silencing transcription factor REST (repressor element-1 silencing transcription factor)/NRSF (neuron-restrictive silencing factor) and REST-dependent suppression of the AMPA receptor subunit GluR2 in CA1 neurons destined to die. Here we show that REST regulates an additional gene target, OPRM1 (μ opioid receptor 1 or MOR-1). MORs are abundantly expressed by basket cells and other inhibitory interneurons of CA1. Global ischemia induces a marked decrease in MOR-1 mRNA and protein expression that is specific to the selectively vulnerable area CA1, as assessed by quantitative real-time RT-PCR, Western blotting, and ChlP. We further show that OPRM1 gene silencing is REST-dependent and occurs via epigenetic modifications. Ischemia promotes deacetylation of core histone proteins H3 and H4 and dimethylation of histone H3 at lysine-9 (H3-K9) over the MOR-1 promoter, an signature of epigenetic gene silencing. Acute knockdown of MOR-1 gene expression by administration of antisense oligodeoxynucleotides to hippocampal slices in vitro or injection of the MOR antagonist naloxone to rats in vivo affords protection against ischemia-induced death of CA1 pyramidal neurons. These findings implicate MORs in ischemia-induced death of CA1 pyramidal neurons and document epigenetic remodeling of expression of OPRM1 in CA1 inhibitory interneurons.

Original languageEnglish (US)
Pages (from-to)4170-4175
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number10
DOIs
StatePublished - Mar 6 2007

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Keywords

  • Epigenetic modification
  • Gene silencing
  • Ischemia
  • Neuronal death

ASJC Scopus subject areas

  • General

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