Human voltage-gated Na+ and K+ channel properties underlie sustained fast AP signaling

Human cortical pyramidal neurons are large, have extensive dendritic trees, and yet have surprisingly fast input-output properties: rapid subthreshold synaptic membrane potential changes are reliably encoded in timing of action potentials (APs). Here, we tested whether biophysical properties of voltage-gated sodium (Na+) and potassium (K+) currents in human neurons can explain their fast input-output properties. Human Na+ and K+ currents had depolarized voltage-dependence, slower inactivation and exhibited a faster recovery from inactivation than their mouse counterparts. Computational modeling showed that despite lower Na+ channel densities in human neurons, the biophysical properties of Na+ channels resulted in higher channel availability and explained fast AP kinetics stability. Finally, human Na+ channel properties also resulted in a larger dynamic range for encoding of subthreshold membrane potential changes. Thus, biophysical adaptations of voltage-gated Na+ and K+ channels enable fast input-output properties of large human pyramidal neurons. One-Sentence Summary Biophysical properties of Na+ and K+ ion channels enable human neurons to encode fast inputs into output.