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.