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.