Impaired Firing and Cell-Specific Compensation in Neurons Lacking Nav1.6 Sodium Channels

Abstract

The ability of neurons to fire precise patterns of action potentials is critical for encoding inputs and efficiently driving target neurons. At the axon initial segment and nodes of Ranvier, where nerve impulses are generated and propagated, a high density of Na_v1.2 sodium channels is developmentally replaced by Na_v1.6 channels. In retinal ganglion cells (GCs), this isoform switch coincides with the developmental transition from single spikes to repetitive firing. Also, Na_v1.6 channels are required for repetitive spiking in cerebellar Purkinje neurons. These previous observations suggest that the developmental appearance of Na_v1.6 underlies the transition to repetitive spiking in GCs. To test this possibility, we recorded from GCs of med (Na_v1.6-null) and wild-type mice during postnatal development. By postnatal day 18, when the switch to Na_v1.6 at GC initial segments is normally complete, the maximal sustained and instantaneous firing rates were lower in med than in wild-type GCs, demonstrating that Na_v1.6 channels are necessary to attain physiologically relevant firing frequencies in GCs. However, the firing impairment was milder than that reported previously in med Purkinje neurons, which prompted us to look for differences in compensatory sodium channel expression. Both Na_v1.2 and Na_v1.1 channels accumulated at initial segments and nodes of med GCs, sites normally occupied by Na_v1.6. In med Purkinje cells, only Na_v1.1 channels were found at initial segments, whereas in other brain regions, only Na_v1.2 was detected at med initial segments and nodes. Thus, compensatory mechanisms in channel isoform distribution are cell specific, which likely results in different firing properties.