Na ⁺ /Ca ²⁺ exchanger triggers transient disruption of axon initial segments in hippocampal granule cells after brief ischemia

The axon initial segment (AIS) is the site of action potential initiation in many cell types. The large density of Na ⁺ channels and the small intraluminal volume of the AIS underlie the largest spike-dependent Na ⁺ raise along the neuron. Our Na ⁺ and Ca ²⁺ imaging experiments in dentate granule cells reveal that the Na ⁺ /Ca ²⁺ exchanger contributes to fast Na ⁺ clearance at the expense of Ca ²⁺ entry specifically at the AIS during short bursts of action potentials. The AIS is thought to be irreversibly disrupted during brain ischemia by the Ca ²⁺ - dependent protease calpain, as an early step leading to neuronal death. We find here that brief transitory ischemia produces a similar calpain-dependent disruption of the AIS in the dentate gyrus. However, this is not an irreversible process: a few days following the brief ischemic stress, intact initial segments re-appear, and calpain activity in the dentate gyrus returns to normal. Moreover, pharmacological blockade of Ca ²⁺ entry through the Na ⁺ /Ca ²⁺ exchanger prevents AIS disruption in vivo and in slice preparations. Our results unveil a highly dynamic anoxia driven disruption-reconstruction of AIS, which is mediated by a previously unnoticed Ca ²⁺ entry through the Na ⁺ /Ca ²⁺ exchanger in the axon initial segment of hippocampal granule cells.