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• W2073701447 abstract "Sensory cells of the vertebrate eye, ear, and vestibular system respond to their stimuli with membrane polarizations that are graded with intensity. These analog-type responses, rather than the binary-like potential changes produced by voltage-gated sodium action potentials, enable the sensory receptors to encode fine gradations of light, sound, or movement. Graded potential sensory neurons, which includes photoreceptors, retinal bipolar cells, hair cells of the auditory and vestibular organs, and electroreceptors in fish selectively express both sustained L-type calcium channels and ribbon-like structures in their synaptic terminals. Spiking neurons typically express faster activating and inactivating non-L channels and exhibit ribbonless synaptic structures. The ribbons and L-type calcium channels are thought to facilitate and regulate graded, tonic release of synaptic transmitter from the sensory neurons. The preponderance of evidence to date has failed to demonstrate sodium-dependent action potentials in these ribbon-containing cells. Consequently, the idea of a graded analog response coupled to graded synaptic release remained internally consistent. The theoretical advantages of this tonic system, versus a digital one using sodium action potentials, are that both increments and decrements of a stimulus can be detected and transmitted easily. Moreover, graded synapses can transmit higher rates of information than spike driven synapses (Juusola and French 1997Juusola M. French A.S. Neuron. 1997; 18: 959-968Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar), which would seem to be a prudent design feature for the detector circuitry in a sensory system. Now, however, the doctrine of graded transduction and signal transfer is being challenged. In this issue of Neuron, Kawai et al. 2001Kawai F. Horiguchi M. Suzuki H. Miyachi E.-i. Neuron. 2001; 30 (this issue,): 451-458Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar demonstrate that rod photoreceptors in human retina express voltage-gated sodium currents. These authors, a group from a very small cadre of investigators who have ever recorded from neurons of human retina, perform whole-cell patch-pipet recordings from rods in small pieces of retina that were removed from human eyes during ophthalmic surgery. Kawai et al. 2001Kawai F. Horiguchi M. Suzuki H. Miyachi E.-i. Neuron. 2001; 30 (this issue,): 451-458Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar demonstrate that in a majority of the rods, membrane depolarizations evoke brief action potentials that are not affected by cobalt, a calcium channel blocker, but are suppressed by TTX. These authors suggest that sodium-dependent action potentials might be an inherent part of light-evoked responses in these sensory neurons. A novel aspect of Kawai et al.'s finding is that multitudes of previous studies in rods and cones of amphibians, reptiles, fish, and even monkeys have never demonstrated voltage-gated sodium currents. Interestingly, however, two recent studies have discovered voltage-gated sodium currents in subclasses of retinal bipolar cell in rat and goldfish (Pan and Hu 2000Pan Z.H. Hu H.J. J. Neurophysiol. 2000; 84: 2564-2571PubMed Google Scholar, Zenisek et al. 2001Zenisek, D., Henry, D., Studholme, K., Yazulla, S., and Matthews, G. (2001). J. Neurosci., in press.Google Scholar). Furthermore, Jagger et al. 1999Jagger D.J. Holley M.C. Ashmore J.F. Pflugers Arch. 1999; 438: 8-14Crossref PubMed Scopus (11) Google Scholar reported voltage-gated sodium currents in hair cell precursors. Perhaps voltage-gated sodium currents play a broader role in sensory processing in the graded potential, ribbon-containing neurons than previously thought. Given the uniqueness of this finding in rods by Kawai et al. 2001Kawai F. Horiguchi M. Suzuki H. Miyachi E.-i. Neuron. 2001; 30 (this issue,): 451-458Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, one immediately wonders whether the expression of voltage-gated currents in human rods reflects a pathophysiological state of these cells. In the eye, retinal pigmented epithelial cells (RPE) form a single layered sheet that abuts the photoreceptor outer segments. In rat, monkey, and human retinas, freshly isolated RPE cells are devoid of TTX-sensitive voltage-gated currents. After a short time in culture, however, these cells express robust voltage-gated sodium currents (Wen et al. 1994Wen R. Lui G.M. Steinberg R.H. J. Physiol. 1994; 476: 187-196Crossref PubMed Scopus (40) Google Scholar, Botchkin and Matthews 1994Botchkin L.M. Matthews G. Proc. Natl. Acad. Sci. USA. 1994; 91: 4564-4568Crossref PubMed Scopus (30) Google Scholar). A logical question is whether the rods used in this study by Kawai et al. 2001Kawai F. Horiguchi M. Suzuki H. Miyachi E.-i. Neuron. 2001; 30 (this issue,): 451-458Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar could have progressed through a transdifferentiation similar to that of the RPE cells. A majority of the rods in the Kawai et al. study were taken from pieces of retina that had been detached in the eye for an unknown period of time. However, voltage-gated sodium currents were also observed in three rods recorded from tissue excised from a nondetached retina. On the assumption that the preparation of the rods for recording didn't somehow change the characteristics of these cells, this finding adds credence to the idea that the sodium channels are expressed normally in human rods. The question then turns to why these currents are seen only in human rods and not in other classes of animal. Could the exclusive expression of voltage-gated sodium currents in human rods reflect a structural specialization of human retina? Kawai et al. 2001Kawai F. Horiguchi M. Suzuki H. Miyachi E.-i. Neuron. 2001; 30 (this issue,): 451-458Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar suggest that voltage-gated sodium currents might be necessary to amplify the transmission of the light-evoked signals along lengthy axons to the synaptic terminals of the rods. Based on the location of the recorded rods in the retina, this idea is probably not valid. A unique feature of primate retina is the fovea, a region that is specialized for high acuity vision. In the fovea, second and third order neurons, the bipolar and ganglion cells, are physically displaced from the photoreceptors. Consequently, axons of cones, the only photoreceptor class in this area, extend laterally for distances up to 300 μm to make synapses onto bipolar cells. It could be argued that that sodium action potentials might enhance signal transfer from the cell bodies to the synaptic terminals of foveal cones with their long axons. However, the rods recorded by Kawai et al. were obtained from retina more than 20 mm from the center of the fovea. The axons of these rods are very much shorter than those of the foveal cones. A recent morphological study of human retina revealed that in peripheral retina (distances greater than 2.5 mm from the center of the fovea) axons of both rods and cones are very short and the displacement of bipolar and ganglion cells is negligible (Sjostrand et al. 1999Sjostrand J. Popovic Z. Conradi N. Marshall J. Graefes Arch.Clin. Exp. Ophthalmol. 1999; 237: 1014-1023Crossref Scopus (52) Google Scholar). Therefore, from a morphological standpoint, no obvious need for action potentials in human rods is evident. Under what circumstances might the voltage-gated sodium currents be involved in signaling visual stimuli by photoreceptors and bipolar cells in retina? Definitive experiments to answer this question remain to be done. However, a consideration of the voltage and kinetic characteristics of the sodium currents does limit the possibilities. At the typical range of resting potentials reported for photoreceptors and bipolar cells (−55 mV to −30 mV), voltage-gated sodium currents would be moderately inactivated. In rat bipolar cells and human rods, the half-maximum inactivation voltages for voltage-gated sodium currents are −68 and −65 mV, respectively (Pan and Hu 2000Pan Z.H. Hu H.J. J. Neurophysiol. 2000; 84: 2564-2571PubMed Google Scholar, Kawai et al. 2001Kawai F. Horiguchi M. Suzuki H. Miyachi E.-i. Neuron. 2001; 30 (this issue,): 451-458Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). In order to fire an action potential, the membrane potential would have to be hyperpolarized well below the resting potential and then depolarized by several tens of millivolts. In rat bipolar cells and human rods, the half-maximum activation voltages for these sodium currents are −27 mV and −35 mV, respectively. Consequently, the rods and OFF bipolar cells would only be expected to fire an action potential when a bright light stimulus was decreased or turned off. In the ON bipolar cells, which depolarize to light, voltage-gated sodium currents would manifest themselves when light was increased. Whether an action potential would actually be generated under any these stimulus conditions would depend on other factors. For example, the magnitude of the voltage-gated sodium current must be large enough to offset competing outward currents, such as voltage-gated potassium currents, that would keep the membrane hyperpolarized (Barnes 1994Barnes S. Neuroscience. 1994; 58: 447-459Crossref PubMed Scopus (64) Google Scholar, Kawai et al. 2001Kawai F. Horiguchi M. Suzuki H. Miyachi E.-i. Neuron. 2001; 30 (this issue,): 451-458Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). Future experiments in which the effects of TTX on light responses recorded from photoreceptors and bipolar cells will help to settle these questions directly. Analyses of sodium currents in bipolar cells and neurotransmitter-gated currents from neurons postsynaptic to these cells are consistent with the notion that sodium-dependent action potentials are not in the physiological synaptic signaling repertoire of the bipolar cells. Nonetheless, subthreshold voltage-gated sodium-dependent currents may still facilitate signal transfer in the dendrites. In the subclasses of the bipolar cells that expressed these channels, Zenisek et al. 2001Zenisek, D., Henry, D., Studholme, K., Yazulla, S., and Matthews, G. (2001). J. Neurosci., in press.Google Scholar, using both immunological and electrophysiological approaches, localized the voltage-gated sodium channels to the dendrites and somas of these cells. Channels were not expressed near the synaptic terminals. Based on the low density of these channels compared to other spiking neurons, and their localization, these authors propose that subthreshold sodium currents serve to boost depolarizing synaptic currents in a manner similar to that proposed for CNS neurons (Cook and Johnston 1999Cook E.P. Johnston D. J. Neurophysiol. 1999; 81: 535-543Crossref PubMed Scopus (63) Google Scholar). Two arguments suggest that even if sodium action potentials were generated in bipolar cells, this digital signal is not likely to be synaptically transmitted to postsynaptic neurons. If TTX-sensitive action potentials modulated vesicular glutamate release from the bipolar cells, one would expect to see occasional multiquantal spontaneous events in neurons driven by bipolar cells. At synapses between neurons from the CNS, TTX suppression of spontaneous, larger amplitude events is commonly observed. In contrast, Tian et al. 1998Tian N. Hwang T.N. Copenhagen D.R. J. Neurophysiol. 1998; 80: 1327-1340PubMed Google Scholar found no evidence for TTX-sensitive, larger amplitude, glutamate-mediated, spontaneous synaptic events in mouse retinal ganglion cells. This strongly suggests that sodium-dependent action potentials play a very minor role in modulating release from bipolar cells. From a hypothetical standpoint, it can be argued that it is inefficient to use sodium-action potentials to modulate neurotransmitter release from photoreceptor or bipolar cell synapses. In both of these cell types, exocytosis is coupled to calcium influx through L-type channels (Tachibana et al. 1993Tachibana M. Okada T. Arimura T. Kobayashi K. et al.J. Neurosci. 1993; 13: 2898-2909PubMed Google Scholar, Schmitz and Witkovsky 1997Schmitz Y. Witkovsky P. Neuroscience. 1997; 78: 1209-1216Crossref PubMed Scopus (114) Google Scholar). Recently, Mermelstein et al. 2000Mermelstein P.G. Bito H. Deisseroth K. Tsien R.W. J. Neurosci. 2000; 20: 266-273Crossref PubMed Google Scholar reported that in terms of calcium influx through voltage-gated calcium channels, action potentials are more effectively coupled to non-L-type calcium channels. The slower activation kinetics of the L-type channels were more efficiently activated by kinetically slower membrane potential changes. Further work will be needed to establish whether the fast sodium spikes of human rods can regulate glutamate release from these cells. Kawai et al.'s report of voltage-gated sodium currents in human rods forces us to reexamine the role of these regenerative currents in the transduction and signaling of sensory information. Reports of similar currents in retinal bipolar cells adds weight to the notion that the voltage-gated sodium currents are integral components of what was formerly thought to be a graded potential, analog system of signal detection and transmission. Critical experiments for the future will be to ascertain if and how these sodium currents influence the light-driven responses in the bipolar and photoreceptor cells of the retina. At first glance, it would seem improbable that full-fledged sodium action potentials would play a major role. Thus, the first stages of retinal processing are likely to remain analog rather than digital. However, subthreshold regenerative sodium currents might provide a small boost in signal processing." @default.
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• W2073701447 date "2001-05-01" @default.
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• W2073701447 title "Is the Retina Going Digital?" @default.
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