Transient ischemia, like that seen during stroke, causes the death of some neurons--particularly CA1 pyramidal neurons of the hippocampus--but not others. Susceptibility is associated with influx of Ca2+ or Zn2+, or both, through AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid) receptor channels, which are receptors for the neurotransmitter glutamate. New experiments by Liu et al. show clearly that these channels are indeed the culprits. Not all AMPA channels conduct Ca2+, and it is the GluR2 subunit that determines this specificity. Liu et al., therefore, used viral vectors injected into rat hippocampus to express a mutant GluR2(R) subunit, which assembles into Ca2+-impermeable channels. This prevented permeability of AMPA channels to Ca2+ or Zn2+ and protected the CA1 pyramidal cells from injury induced by ischemia. Conversely, the authors used similar methods to express Ca2+-permeable [GluR2(Q)] channels in neurons in the CA3 area and dentate gyrus that are normally not susceptible to ischemic injury. Granule cells that expressed the Ca2+-permeable channel underwent cell death after an ischemic insult. The authors note that therapeutic strategies aimed at protecting brain cells by inhibiting AMPA receptors are problematic because useful actions of glutamate in uninjured cells are also blocked. The new studies suggest that selective inhibition of Ca2+ permeability of AMPA receptor channels, which would leave other receptor functions unaffected, may offer a more promising strategy.
S. Liu, L. Lau, J. Wei, D. Zhu, S. Zou, H.-S. Sun, Y. Fu, F. Liu, Y. Lu, Expression of Ca2+-permeable AMPA receptor channels primes cell death in transient forebrain ischemia. Neuron 43, 43-55 (2004). [Online Journal]