The AMPAR subunit GluR2: Still front and center-stage

Abnormal influx of Ca²⁺ through AMPA-type glutamate receptors (AMPARs) is thought to contribute to the neuronal death associated with a number of brain disorders. AMPARs exist as both Ca²⁺-impermeable and Ca²⁺-permeable channels. AMPARs are encoded by four genes designated GluR1 (GluR-A) through GluR4 (GluR-D). The presence of the GluR2 subunit renders heteromeric AMPA receptor assemblies Ca²⁺-impermeable. Molecular diversity of AMPARs under physiological and pathological conditions is generated by differential spatio-temporal patterns of GluR expression, by alternative RNA splicing and editing and by targeting and trafficking of receptor subunits at dendritic spines. The GluR2 gene is under transcriptional control by the RE1 element specific transcription factor, a gene silencing factor which renders it neuron-specific. GluR2 transcripts are edited by ADAR2 (double-stranded RNA-specific editase 1). AMPAR targeting and trafficking to spines are regulated by synaptic activity and are critical to synaptic plasticity. Recent studies involving animal models of transient forebrain ischemia and epilepsy show that GluR2 mRNA and GluR2 subunit expression are downregulated in vulnerable neurons prior to cell death. Ca²⁺ imaging and electrical recording from individual pyramidal neurons in hippocampal slices reveal changes in AMPAR functional properties after ischemia. In slices from post-ischemia animals, CA1 neurons with robust action potentials exhibit greatly enhanced AMPA-elicited rises in intracellular Ca²⁺. Excitatory postsynaptic currents in post-ischemic CA1 exhibit an enhanced Ca²⁺-dependent component that appears to be mediated by Ca²⁺-permeable AMPARs. These studies provide evidence for Ca²⁺ influx through AMPARs in neurons destined to die. To examine whether acute GluR2 downregulation, even in the absence of a neurological insult, can induce neuronal death, we performed knockdown experiments in rats and gerbils with antisense oligonucleotides targeted to GluR2 mRNA. GluR2 antisense oligonucleotide induced neuronal cell death of pyramidal neurons and enhanced pathogenicity of brief ischemic episodes. These observations provide evidence for Ca²⁺ influx through AMPARs in neurons destined to die and implicate Ca²⁺-permeable AMPARs in the pathogenesis of ischemia-induced neuronal death. Copyright (C) 2000 Elsevier Science B.V.