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

Research output: Contribution to journalArticle

103 Citations (Scopus)

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

Fingerprint

Opioid Receptors
Transcriptional Silencer Elements
Epigenomics
Ischemia
Transcription Factors
Neurons
Pyramidal Cells
Gene Silencing
Histones
Interneurons
Oligodeoxyribonucleotides
Naloxone
Lysine
Real-Time Polymerase Chain Reaction
Proteins
Cell Death
Western Blotting
Gene Expression
Messenger RNA
Injections

Keywords

  • Epigenetic modification
  • Gene silencing
  • Ischemia
  • Neuronal death

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Ischemic insults promote epigenetic reprogramming of μ opioid receptor expression in hippocampal neurons. / Formisano, Luigi; Noh, Kyung Min; Miyawaki, Takahiro; Mashiko, Toshihiro; Bennett, Michael V. L.; Zukin, R. Suzanne.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 10, 06.03.2007, p. 4170-4175.

Research output: Contribution to journalArticle

@article{1d6a87fa350447f68a5d73f8befd6409,
title = "Ischemic insults promote epigenetic reprogramming of μ opioid receptor expression in hippocampal neurons",
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.",
keywords = "Epigenetic modification, Gene silencing, Ischemia, Neuronal death",
author = "Luigi Formisano and Noh, {Kyung Min} and Takahiro Miyawaki and Toshihiro Mashiko and Bennett, {Michael V. L.} and Zukin, {R. Suzanne}",
year = "2007",
month = "3",
day = "6",
doi = "10.1073/pnas.0611704104",
language = "English (US)",
volume = "104",
pages = "4170--4175",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "10",

}

TY - JOUR

T1 - Ischemic insults promote epigenetic reprogramming of μ opioid receptor expression in hippocampal neurons

AU - Formisano, Luigi

AU - Noh, Kyung Min

AU - Miyawaki, Takahiro

AU - Mashiko, Toshihiro

AU - Bennett, Michael V. L.

AU - Zukin, R. Suzanne

PY - 2007/3/6

Y1 - 2007/3/6

N2 - 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.

AB - 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.

KW - Epigenetic modification

KW - Gene silencing

KW - Ischemia

KW - Neuronal death

UR - http://www.scopus.com/inward/record.url?scp=34247185756&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34247185756&partnerID=8YFLogxK

U2 - 10.1073/pnas.0611704104

DO - 10.1073/pnas.0611704104

M3 - Article

C2 - 17360495

AN - SCOPUS:34247185756

VL - 104

SP - 4170

EP - 4175

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 10

ER -