Neuron morphology influences axon initial segment plasticity

ABSTRACT

In most vertebrate neurons, action potentials are initiated in the axon initial segment (AIS), a specialized region of the axon containing a high density of voltage-gated sodium and potassium channels. It has recently been proposed that neurons use plasticity of AIS length and/or location to regulate their intrinsic excitability. Here we quantify the impact of neuron morphology on AIS plasticity using computational models of simplified and realistic somatodendritic morphologies. In small neurons (e.g., dentate granule neurons), excitability was highest when the AIS was of intermediate length and located adjacent to the soma. Conversely, neurons having larger dendritic trees (e.g., pyramidal neurons) were most excitable when the AIS was longer and/or located away from the soma. For any given somatodendritic morphology, increasing dendritic membrane capacitance and/or conductance favored a longer and more distally located AIS. Overall, changes to AIS length, with corresponding changes in total sodium conductance, were far more effective in regulating neuron excitability than were changes in AIS location, while dendritic capacitance had a larger impact on AIS performance than did dendritic conductance. The somatodendritic influence on AIS performance reflects modest soma-to-AIS voltage attenuation combined with neuron-size-dependent changes in AIS input resistance, effective membrane time constant, and isolation from somatodendritic capacitance. We conclude that the impact of AIS plasticity on neuron excitability will depend largely on somatodendritic morphology, and that, in some neurons, a shorter or more distally located AIS may promote, rather than limit, action potential generation.

Significance Statement: Action potentials in vertebrate neurons are initiated in the axon initial segment (AIS), a specialized region of axon containing a high density of voltage-gated sodium channels. It has been proposed that neurons regulate their intrinsic excitability via plastic changes in AIS length and/or location. Here we employ computational modeling to quantify the impact of AIS plasticity across a range of simplified and realistic neuron morphologies. We demonstrate that somatodendritic morphology will dictate both the magnitude and direction of excitability changes occurring in response to AIS plasticity. Excitability of large neurons is enhanced when the AIS is longer and/or distal from the soma, while small neurons are most excitable when the AIS is of intermediate length and/or adjacent to the soma.