Inactivation of axonal sodium channels: implications for excitability and synaptic transmission – AXODE

While there has been a considerable amount of work on ionic channels expressed at the soma and on dendrites, in comparison the axon is a neuronal compartment that remains largely unexplored. This lack of data is principally due to the experimental difficulty to obtain direct recording from this neuronal compartment. This project uses axonal electrophysiology techniques, in particular recordings in axonal blebs created by the slicing procedure, as well as pharmacological manipulations. In addition, biophysical theory and simulation of morphologically detailed models are used and experimentally tested.

Classically, it is considered that electrical communication between neurons is all-or-none. We have found that axonal sodium channel inactivation results in the modulation of transmission, so that synaptic communication is gradual. This phenomenon greatly enhances the information transmitted by neurons.

The final perspective of the project is to understand how the input signals integrated at the soma are transformed into spike trains carried through the axon, and how spikes impact postsynaptic neurons, as a function of previous somatic events in the presynaptic neuron. The project questions two major dogmas in neurophysiology: that neurons fire a spike when the membrane potential reaches a fixed threshold; that spikes are binary events.

We have published 5 articles in international journals since the start of this project, including 1 in J Neuroscience, 1 in Nature Communications (about gradual synaptic transmission) and one in PLoS Computational Biology (about sharp spike initiation).

Action potentials are generated in central neurons by the opening of sodium (Na) channels in the axon initial segment. Thus, Na channels are primary determinants of neuronal excitability and alteration in their properties often leads to neurological diseases. Among the nine cloned subunits of voltage-gated Na (Nav) channels, three types are encountered in central neurons: Nav1.1, Nav1.2 and Nav1.6. Nav channels in the axon not only promote spike initiation and forward propagation but also favour back-propagation towards the soma and dendrites and also support burst firing. Nav channels in the axon display peculiar biophysical properties. At resting membrane potential, Na channels are inactivated by 90-95% in the axon of hippocampal and neocortical neurons. The consequences of this strong inactivation have not been clearly estimated, but two major implications can be anticipated. First, variations of the membrane potential with synaptic input should strongly modulate the availability of axonal Na channels, which would in turn modulate the threshold for spike initiation. This would mean that a neuron’s output is determined by the interplay between synaptic inputs and a dynamic spike threshold. Second, variations in the availability of axonal Na channels may also modulate spike shape in the axon. As a result, synaptic transmission may be modulated by the presynaptic membrane potential. This would make spikes graded events, rather than all-or-none events.

Thus the inactivation of axonal Na channels may have major consequences for neural function: on the modulation of excitability, and on synaptic transmission. In this project, we propose to investigate the impact of Na channel inactivation on excitability (part 1) and on axonal spike shape and synaptic transmission (part 2), using a combination of experimental and theoretical approaches. The consortium consists of two groups with complementary expertise: 1) the group of Romain Brette (Institut de la Vision, UPMC/INSERM/CNRS, Paris), expert in computational neuroscience ; 2) the group of Dominique Debanne (INSERM, Marseille), expert in axon neurophysiology.