Molecular and cellular mechanisms underlying ischemia-induced neuronal death
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Transient global ischemia, arising due to cardiac arrest induces selective, delayed death of hippocampal CA1 neurons. Although the mechanisms underlying ischemia-induced death are as yet unclear, the substantial delay between insult and neuronal death suggests a critical role for transcriptional changes. The transcriptional repressor REST plays a strategic role in neuronal phenotype. In neural progenitors and non-neuronal cells, REST represses a large array of neural specific genes including the AMPA receptor subunit GluR2. The GluR2 subunit is crucial in determining AMPAR function. Principal neurons of hippocampus express primarily GluR2-containing AMPARs; thus, an acute reduction in GluR2 could have profound consequences for neuronal survival. Here I determined the functional properties of synaptic AMPARs in post-ischemic hippocampus and examined a causal role for GluR2-lacking AMPARs in the late rise in intracellular Zn2+ and neuronal death. At 42 h after ischemia, AMPA-EPSCs exhibited pronounced inward rectification and marked sensitivity to 1-naphthyl acetyl spermine (Naspm), a selective channel blocker of GluR2-lacking AMPARs. In control hippocampus, AMPA-EPSCs were electrically linear and relatively insensitive to Naspm. Naspm, injected intrahippocampally at 9 to 40 h after insult, greatly reduced the late rise in intracellular free Zn2+ in post-ischemic CA1 neurons and afforded partial protection against ischemia-induced cell death. The precise mechanisms underlying the switch in AMPAR phenotype remain controversial. Here I show that REST acts via epigenetic modifications to silence GluR2 expression and remodel the AMPAR phenotype in adult hippocampal neurons. Ischemic insults promote assembly of the transcriptional repressor REST, CoREST and mSin3A (the REST-core pressor complex) over the GluR2 promoter specifically in neurons destined to die. The REST-corepressor complex promotes deacetylation of core histone protein H3, dimethylation of H3 at lysine 9, but not lysine 4, and association with McCP2, an epigenetic signature of gene silencing. Inhibition of REST by delivery of recombinant mutant protein REST (REST-VP16) or REST RNA interference into the hippocampus of rats by means of the lentivirus expression system rescues GluR2 expression and ameliorates hippocampal injury. These findings document a causal role for REST-dependent epigenetic remodeling of GluR2 in ischemic cell death and identify REST as a novel therapeutic target for ischemic stroke.