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Alex E Hadjinicolaou, Paul Werginz, Vineeth Raghuram, Frank Rattay, Shelley I Fried; Sodium channel band expression in the AIS: fundamentals of activation threshold. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3583. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The selective activation of major retinal ganglion cell (RGC) types constitutes a key goal of the stimulation paradigms used by retinal prosthetics as it can greatly enhance the quality of visual perception that can be restored to the blind. We hypothesize that (1) electrical responses are governed by the expression of voltage-gated sodium channels (Nav) within the sodium channel band (SCB) on the axon initial segment (AIS); and (2) knowledge of sodium channel expression in RGC types will inform a more effective stimulation paradigm in next-generation retinal prostheses.
Cell-attached patch clamp recordings were taken from brisk-transient and brisk-sustained RGCs in explanted whole-mount New Zealand White rabbit retina (n=8). High-resolution maps (5 μm point grid) of RGC activation threshold were collected for each recorded cell using a single platinum/iridium stimulating electrode of 1 MΩ impedance (Microprobes, MD), positioned 5 μm above the retinal inner limiting membrane. Stimulus waveforms comprised of pulse trains delivered at 10 Hz and featured cathodic-first, biphasic current pulses with 100 μm phase duration and zero interphase duration. At each stimulus electrode location, a series of 4-5 pulses with amplitude increasing by 1-2 μA per pulse (0.5 μA for highly sensitive regions) was delivered and repeated six times. Threshold (defined as the level of current for which 50% of delivered pulses evoke an action potential) was determined for each location by plotting the number of evoked spikes against pulse amplitude, and by fitting a sigmoidal curve to the data.
All recorded RGCs (n=10) featured a low-threshold region (LTR) within their respective "threshold map" that was coextensive with the SCB. Further, most LTRs revealed a characteristic drop in threshold when moving from proximal to distal AIS. Preliminary modelling results demonstrate that this drop in threshold can be largely attributed to certain SCB properties (e.g. ratio of Nav1.6/Nav1.1).
Our results suggest that subtle differences in SCB composition can underlie dramatic differences in the ability of ganglion cells to respond to electrical stimulation.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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