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.