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 unexpectedly 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 pyramidal neurons can explain their fast input-output properties. Human Na⁺ and K⁺ currents exhibited more depolarized voltage dependence, slower inactivation, and faster recovery from inactivation compared with 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 contributed to fast AP kinetics stability. Last, 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.