Expression of Ca2+-Permeable AMPA receptor channels primes cell death in transient forebrain ischemia

CA1 pyramidal neurons degenerate after transient global ischemia, whereas neurons in other regions of the hippocampus remain intact. A step in this selective injury is Ca2+ and/or Zn2+ entry through Ca2+-permeable AMPA receptor channels; reducing Ca2+ permeability of AMPA receptors via expression of Ca2+-impermeable GluR2(R) channels or activation of CRE transcription in the hippocampus of adult rats in vivo using shutoff-deficient pSFV-based vectors rescues vulnerable CA1 pyramidal neurons from forebrain ischemic injury. Conversely, the induction of Ca2+ and/or Zn2+ influx through AMPA receptors by expressing functional Ca2+-permeable GluR2(Q) channels causes the postischemic degeneration of hippocampal granule neurons that otherwise are insensitive to ischemic insult. Thus, the AMPA receptor subunit GluR2 gates entry of Ca2+ and/or Zn2+ that leads to cell death following transient forebrain ischemia.