Na +/Ca 2+ exchanger 2 is neuroprotective by exporting Ca 2+ during a transient focal cerebral ischemia in the mouse

Abstract

Na +/Ca 2+ exchanger (NCX), by mediating Na + and Ca 2+ fluxes bi-directionally, assumes a role in controlling the Ca 2+ homeostasis in the ischemic brain. It has been suggested that the three isoforms of NCX (NCX1, 2 and 3) may be differentially involved in permanent cerebral ischemia. However, the role of NCX2 has not been defined in ischemic reperfusion injury after a transient focal cerebral ischemia. Furthermore, it is not known whether NCX2 imports or exports intracellular Ca 2+ ([Ca 2+] i) following ischemia and reperfusion. To define the role of NCX2 in ischemia and reperfusion, we examined mice lacking NCX2, in vivo and in vitro. After an in vitro ischemia, a significantly slower recovery in population spike amplitudes, a sustained elevation of [Ca 2+] i and an increased membrane depolarization were developed in the NCX2-deficient hippocampus. Moreover, a transient focal cerebral ischemia in vivo produced a larger infarction and more cell death in the NCX2-deficient mouse brain. In particular, in the wild type brain, NCX2-expressing neurons were largely spared from cell death after ischemia. Our results suggest that NCX2 exports Ca 2+ in ischemia and thus protects neuronal cells from death by reducing [Ca 2+] i in the adult mouse brain.