Ischemic insults derepress the gene silencer REST in neurons destined to die

Agata Calderone, Teresa Jover, Kyung Min Noh, Hidenobu Tanaka, Hidenori Yokota, Ying Lin, Sonja Y. Grooms, Roodland Regis, Michael V. L. Bennett, R. Suzanne Zukin

Research output: Contribution to journalArticlepeer-review

281 Scopus citations


A subset of genes implicated in genetic and acquired neurological disorders encode proteins essential to neural patterning and neurogenesis. The gene silencing transcription factor neuronal repressor element-1 silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF) plays a critical role in elaboration of the neuronal phenotype. In neural progenitor and non-neural cells, REST acts by repression of a subset of neural genes important to synaptic plasticity and synaptic remodeling, including the AMPA receptor (AMPAR) subunit GluR2. Here we show that global ischemia triggers REST mRNA and protein expression. REST suppresses GluR2 promoter activity and gene expression in neurons destined to die. Because the GluR2 subunit governs AMPAR Ca2+ permeability, these changes are expected to have profound effects on neuronal survival. In keeping with this concept, acute knockdown of the REST gene by antisense administration prevents GluR2 suppression and rescues post-ischemic neurons from ischemia-induced cell death in an in vitro model. To our knowledge, our study represents the first example of ischemia-induced induction of a master transcriptional regulator gene and its protein expression critical to neural differentiation and patterning in adult neurons. Derepression of REST is likely to be an important mechanism of insult-induced neuronal death.

Original languageEnglish (US)
Pages (from-to)2112-2121
Number of pages10
JournalJournal of Neuroscience
Issue number6
StatePublished - Mar 15 2003


  • AMPA receptors
  • Chromatin remodeling
  • Global ischemia
  • Hippocampus
  • Neuronal death
  • Neuronal insult
  • REST
  • Transcription factors

ASJC Scopus subject areas

  • Neuroscience(all)


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