Axonal Sodium-Channel Bands Shape the Response to Electric Stimulation in Retinal Ganglion Cells

Abstract

Electric stimulation of the retina reliably elicits light percepts in patients blinded by outer retinal diseases. However, individual percepts are highly variable and do not readily assemble into more complex visual images. As a result, the quality of visual information conveyed to patients has been quite limited. To develop more effective stimulation methods that will lead to improved psychophysical outcomes, we are studying how retinal neurons respond to electric stimulation. The situation in the retina is analogous to other neural prosthetic applications in which a better understanding of the underlying neural response may lead to improved clinical outcomes. Here, we determined which element in retinal ganglion cells has the lowest threshold for initiating action potentials. Previous studies suggest multiple possibilities, although all were within the soma/proximal axon region. To determine the actual site, we measured thresholds in a dense two-dimensional grid around the soma/proximal axon region of rabbit ganglion cells in the flat mount preparation. In directionally selective (DS) ganglion cells, the lowest thresholds were found along a small section of the axon, about 40 microm from the soma. Immunochemical staining revealed a dense band of voltage-gated sodium channels centered at the same location, suggesting that thresholds are lowest when the stimulating electrode is closest to the sodium-channel band. The size and location of the low-threshold region was consistent within DS cells, but varied for other ganglion cell types. Analogously, the length and location of sodium channel bands also varied by cell type. Consistent with the differences in band properties, we found that the absolute (lowest) thresholds were also different for different cell types. Taken together, our results suggest that the sodium-channel band is the site that is most responsive to electric stimulation and that differences in the bands underlie the threshold differences we observed.

Response variability to high rates of electric stimulation in retinal ganglion cells

“…Phase durations remained constant at 200 s. For rates of 100 -700 PPS, the interphase delay was equal to one-half of the period between consecutive pulses of the same phase, i.e., for 100 Hz, there was a 5-ms delay between the onset of consecutive cathodal and anodal pulses. Although this approach introduced a variable delay between phases, it allowed the response to the cathodal phase to be studied in isolation, consistent with previous work (Fried et al 2009;Sekirnjak et al 2006). For the 10-PPS rate, the interval between cathodal and anodal was 10 ms, and the rate between anodal and cathodal was determined by the pulse rate.…”

“…In response to short-duration pulses, the location of the sodium channel band has been shown to correspond to the center of the region with the lowest threshold and is generally centered between 20 and 60 m from the soma along the proximal axon (Fried et al 2009). Using an iterative process, we were able to quickly find the center of the low-threshold region: movement of the stimulating electrode toward the center of the low-threshold region resulted in decreasing thresholds, whereas movement away from the center resulted in increasing thresholds.…”

“…One anatomic component that is likely to strongly influence the response to electric stimulation is a dense band of voltage-gated sodium channels located within the proximal axon (Boiko et al 2003;Fried et al 2009;Van Wart et al 2007;Wollner and Catterall 1986); the band was shown to be the site with the highest sensitivity to electric stimulation (Fried et al 2009), and it is therefore likely to be the site at which spikes are first initiated in response to electric stimulation. The anatomic properties of the band are different within each ganglion cell subpopulation (Fried et al 2009), and it is therefore possible that these differences influence the ability of each ganglion cell type to follow pulse trains delivered at high rates. Additional variability may arise from the composition of ion channels within the band.…”

Upper threshold of extracellular neural stimulation

“…Here it can be 2-40 times higher than the average on the soma (Fried et al 2009). For this asymmetric configuration, the sodium channel maximum conductivity was increased 10-fold (to 500 mS/cm 2 ) at the depolarized pole of the cell, accounting for 5% of the total area, as shown in Fig.…”

Projections, Partaken Circuits and Axon Initial Segments of Cortical Principal Neurons

“…Ion channels composition at the AIS can vary considerably across different neuronal types [74] and diversity in the AIS length and position in the axon may also underlie interneuron variation in firing properties. For example, classes of retinal ganglion cells with different visual properties have initial segments that differ in length, and in their position within the axon [98]. In the avian magnocellularis and laminaris nuclei, which are respectively the second-and third-order nuclei in the auditory pathway [99], the length and the location of the AIS vary with the tuning frequency of neurons [100].…”