|Site-directed mRNA editing of sodium channels has potential to alter neuronal firing and network dynamics: Computer models
|Year of Publication
|Lytton, WW., Knox A., & Rosenthal J. J. C.
|Society for Neuroscience 2017 (SFN '17)
|SFN, Society for Neuroscience
mRNA editing offers the potential for targeting transcripts in the living animal or patient, providing the possibility of treatment of underlying genetic diseases. Adenosine deamination in mRNA has was used to alter the conductance of mammalian fast sodiums (Naf) channels (NaV1.4), changing a lysine to an arginine residue in the region of the peptide that determines selectivity – the aspartate-glutamate-lysine-alanine motif DEKA is altered to DERA. The removal of channel selectivity allowed passage of both potassium and sodium through the channel, altering the effective reversal potential of a proportion of these channels. The proportion of wild type (WT) versus edited channels (EC) can be controlled experimentally and will be controllable in vivo. We therefore looked at the effects of changes in the EC/WT proportion in a set of single cell models and in a cortical network model. In the Hodgkin-Huxley model, we demonstrated the expected reduction in action potential amplitude, with increase in EC/WT. At a point related to the size of the modeled axon (input impedance), and to the density of potassium channel, the action potential failed as the sodium channels could no longer source sufficient current to oppose the outward currents. Speed of conduction was also affected by the proportion of mutated channel. This was primarily noticeable at locations far from the axon terminal where a baseline velocity of 2 m/s was reduced by 20% before conduction failure occurred. By contrast, conductance speed near the axon terminal was faster, 10 m/s, and was preserved with increased EC/WT, as current build-up near the high-impedence boundary allowed charge to build up fast enough to compensate for the reduced drive. After compensating for the faster kinetics by reducing overall channel density, similar models could be run at mammalian temperatures as were run in the origianl models at 6.3 C. Modification of sodium channels has the potential for future clinical use for the epilepsies and for pain syndromes.