Neural excitability increases with axonal resistance between soma and axon initial segment

The position of the axon initial segment (AIS) is thought to play a critical role in neuronal excitability. Previous experimental studies have found that a distal shift in AIS position correlates with a reduction in excitability. Yet theoretical work has suggested the opposite, because of increased electrical isolation. A distal shift in AIS position corresponds to an elevation of axial resistance R We therefore examined how changes in R at the axon hillock impact the voltage threshold (V_th) of the somatic action potential in L5 pyramidal neurons. Increasing R by mechanically pinching the axon between the soma and the AIS was found to lower V_th by ∼6 mV. Conversely, decreasing R by substituting internal ions with higher mobility elevated V_th All R -dependent changes in V_th could be reproduced in a Hodgkin-Huxley compartmental model. We conclude that in L5 pyramidal neurons, excitability increases with axial resistance and therefore with a distal shift of the AIS.