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 Ca(2+) and/or Zn(2+) entry through Ca(2+)-permeable AMPA receptor channels; reducing Ca(2+) permeability of AMPA receptors via expression of Ca(2+)-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 Ca(2+) and/or Zn(2+) influx through AMPA receptors by expressing functional Ca(2+)-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 Ca(2+) and/or Zn(2+) that leads to cell death following transient forebrain ischemia.