RESUMO
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.
Assuntos
Canais de Cálcio/metabolismo , Sinalização do Cálcio/genética , Ataque Isquêmico Transitório/metabolismo , Prosencéfalo/metabolismo , Receptores de AMPA/metabolismo , Animais , Animais Recém-Nascidos , Cálcio/metabolismo , Canais de Cálcio/genética , Canais de Cálcio Tipo Q/genética , Canais de Cálcio Tipo Q/metabolismo , Morte Celular/genética , Permeabilidade da Membrana Celular/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Quinase 5 Dependente de Ciclina , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Técnicas In Vitro , Integrases/genética , Integrases/metabolismo , Ativação do Canal Iônico/genética , Ataque Isquêmico Transitório/genética , Ataque Isquêmico Transitório/patologia , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Prosencéfalo/patologia , Ligação Proteica/genética , Células Piramidais/metabolismo , Células Piramidais/patologia , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/genética , Zinco/metabolismoRESUMO
The generation of new neurons in the adult mammalian hippocampus is thought to play a role in repairing the brain after injury. Here, we show that 7 d after focal cerebral ischemia, newly divided cells in the dentate gyrus of adult rats increased to approximately sevenfold, compared with sham controls. In the same area, this enhanced dentate neurogenesis was associated with activation of inducible nitric oxide synthase (iNOS). Inhibition of iNOS by aminoguanidine prevented ischemia-induced neurogenesis in the dentate gyrus. In null mutant mice lacking the iNOS gene, increased neurogenesis was not observed after focal cerebral ischemia. This study demonstrates that expression of iNOS is necessary for ischemia-stimulated cell birth in the dentate gyrus and indicates that activation of iNOS may provide a possible strategy for functional recovery from cerebral ischemic insult.
