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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-03, Vol.104 (10), p.4170-4175
• Main Authors: Formisano, Luigi, Noh, Kyung-Min, Miyawaki, Takahiro, Mashiko, Toshihiro, Bennett, Michael V.L, Zukin, R. Suzanne
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Biological Sciences; Cell Survival; Chromatin; Epigenesis, Genetic; Epigenetics; Gene silencing; Genes; Hippocampus - metabolism; Histones; Histones - metabolism; Insults; Ischemia; Ischemia - metabolism; Male; Messenger RNA; Naloxone - pharmacology; Narcotic Antagonists - pharmacology; Neurons; Neurons - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - metabolism; Receptors, Opioid, mu - physiology; RNA, Messenger - metabolism; Time Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0611704104

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 ChIP. 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.