Inhibition of EphA4 signaling after ischemia–reperfusion reduces apoptosis of CA1 pyramidal neurons

Hippocampal CA1 pyramidal neurons are sensitive to ischemic damage. However, the cellular and molecular mechanisms underlying neuronal cell death caused by ischemia-reperfusion (I/R) are not completely clear. Here, we report that the ephrinA/EphA cell-cell interaction signaling pathway plays an important role in the apoptosis of hippocampal CA1 pyramidal neurons induced by I/R. We found that the expression of ephrinA3 and EphA4 is increased in the CA1 region following transient forebrain ischemia. Blocking ephrinA3/EphA4 interaction by EphA4-Fc, an inhibitor of EphA4, attenuated apoptotic neuronal cell death, likely through the inhibition of caspase-3 activation. These results reveal a novel function of ephrin/Eph signaling in the regulation of apoptosis in CA1 pyramidal neurons after I/R.