FHF-independent conduction of action potentials along the leak-resistant cerebellar granule cell axon.

Katarzyna Dover,Dejan Zecevic,Mitchell Goldfarb,Sathyaa Subramaniyam,Egidio D’Angelo,Christopher Marra,Marko Popovic,Sergio Solinas

doi:10.1038/ncomms12895

Abstract

Neurons in vertebrate central nervous systems initiate and conduct sodium action potentials in distinct subcellular compartments that differ architecturally and electrically. Here, we report several unanticipated passive and active properties of the cerebellar granule cell's unmyelinated axon. Whereas spike initiation at the axon initial segment relies on sodium channel (Nav)-associated fibroblast growth factor homologous factor (FHF) proteins to delay Nav inactivation, distal axonal Navs show little FHF association or FHF requirement for high-frequency transmission, velocity and waveforms of conducting action potentials. In addition, leak conductance density along the distal axon is estimated as <1% that of somatodendritic membrane. The faster inactivation rate of FHF-free Navs together with very low axonal leak conductance serves to minimize ionic fluxes and energetic demand during repetitive spike conduction and at rest. The absence of FHFs from Navs at nodes of Ranvier in the central nervous system suggests a similar mechanism of current flux minimization along myelinated axons.

Highlights

Neurons in vertebrate central nervous systems initiate and conduct sodium action potentials in distinct subcellular compartments that differ architecturally and electrically
Lysates prepared from scrapes of upper and lower filter surfaces were directly analyzed by immunoblotting using an factor homologous factor (FHF) monoclonal antibody that recognizes an epitope common to the A-type isoforms encoded by all four Fhf genes[11] and another monoclonal that detects all voltage-gated sodium channels[12]
When lysates were immunoprecipitated with a mixture of antibodies that recognize all protein isoforms encoded by the Fhf[1] and Fhf[4] genes, a much smaller fraction of sodium channels was detected in the distal axon preparation compared with whole cells (Fig. 1d, right)

Summary

Introduction

Neurons in vertebrate central nervous systems initiate and conduct sodium action potentials in distinct subcellular compartments that differ architecturally and electrically. If distally situated sodium channels were slow to inactivate, allowing for significant temporal overlap between the open states of voltage-gated sodium and potassium channels, sodium influx per spike could be far greater, and conduction of high-frequency spike trains would create a greater energy burden for rapid Na þ /K þ pumping and ATP synthesis. These theoretical considerations motivated our investigation of axonal conductance properties using biochemical, genetic, optical and computational tools. These active properties combined with an unexpectedly low-leak conductance serve to minimize energy expenditure within the ultra-thin axon

Methods

Results

Conclusion