A Reinterpretation of the Relationship between Persistent and Resurgent Sodium Currents

Abstract

The resurgent sodium current (INaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, INaRis thought to drive high rates of repetitive neuronal firing. However, INaRis often studied in combination with the persistent or noninactivating portion of sodium currents (INaP). We used dynamic clamp to test how INaRand INaPindividually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned INaRdoes not scale repetitive firing rates due to its rapid decay at subthreshold voltages and that subthreshold INaPis critical in regulating neuronal firing rate. Adjustments to the voltage-gated sodium conductance model used in these studies revealed INaPand INaRcan be inversely scaled by adjusting occupancy in the slow-inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune INaPand Purkinje neuron repetitive firing rates.