Nano-physiology of the action potential generator
A few tens of micrometers into the axon, special cytosceletal proteins organize those ion channels that generate the action potential (AP) output of a neuron. This organelle, the axon initial segment (AIS), features a corsett-like cytoskeleton with parallel rings of actin, regularly spaced by spectrin fibres . The ion channels are tethered there through an adaptor protein, AnkyrinG. Whether this recently discovered near-crytalline spatial arrangement has any impact on the function of the axon initial segment was unclear, especially as the space constant is only 190 nm, a negligible distance for cellular electrodynamics (Figures 1 and 2B).
Figure 1: Schematic of AIS cytoskeleton.
We succeeded, for the first time, in altering the encoding properties of neurons by means of specific changes to the regular cytoskelton. We found that the qv3J mutation of βIV-spectrin leads to a complete loss of this spectrin isoform. Only βII-spectrin remains to recruit some Na+-channels to the AIS. While the somatic and dendritic Na+-channel densities developed normally, the density in the AIS of mutants remained low over the course of cell maturation. Control cells, on the other hand, incorporated more and more Na+-channels into the AIS during maturation. Mature mutant cells showed a significantly higher AP voltage threshold and their AP waveform lost the rapid initial increase in voltage rate of rise, reflecting a loss of current from the initial segment. As a result, the ability of mutant neurons to encode rapid changes in the input was impaired (Figures 2C). In contrast, peak rate of rise, peak potential, and AP duration appeared virtually unaffected. We conclude that in order to ensure that APs are always initiated in the AIS, the number of axonal Na+-channels must increase as the cells mature, since more and more current is required to depolarize the growing somato-dendritic compartment. A functional C-terminus of βIV-spectrin is essential to provide sufficient numbers of Na+-channel binding sites and thereby maintains the AIS as the AP initiation site and the ability to encode fast changes in the input.
 K. Xu, G. Zhong, X. Zhuang, Science, 339, 6118 452 (2013)
Members working within this Project:Andreas Neef