|
ScienceWeek
NEUROBIOLOGY: ON RAPID EVENTS IN THE RETINA
The following points are made by Kendall J. Blumer (Nature 2004 427:20):
1) Imagine walking out of a dark theater into a bright and sunny Sunday afternoon. You are momentarily blinded, but your eyes rapidly adjust to the change and you continue on your way. For some people with a rare visual defect, however, this momentary blindness can last for up to ten seconds. A similar, but potentially more dangerous, prolonged blindness occurs when these individuals drive from daylight into a darkened tunnel. Moreover, people with this problem also suffer from difficulties in seeing certain moving objects (such as balls thrown during a sporting event). Nishiguchi et al(1) have described a genetic cause of this condition. In so doing, they have revealed that visual perception requires rapid deactivation of the light-stimulated responses shown by neurons in the eye.
2) Light streaming into the eye is detected by specialized neurons (photoreceptors) in the retina. In response to light, a coordinated series of molecular events -- the so-called phototransduction cascade -- is triggered in these cells(2). Photons excite pigment-containing proteins called rhodopsins, which then switch on the protein transducin by loading it with the small molecule guanosine triphosphate (GTP). When bound to GTP, transducin turns on a phosphodiesterase, an enzyme that breaks down cyclic guanosine monophosphate (cGMP -- another small molecule). High concentrations of cGMP open specialized ion channels in the outer cell membrane. Thus, by reducing the concentration of cGMP, light changes the flow of ions across the membrane of photoreceptive neurons, producing an electrical signal that is necessary for communicating with the brain.
3) Once this light-activated switch is on, how do cells turn it off? One mechanism is to limit the amount of time that GTP-bound transducin can keep the phosphodiesterase enzyme active. Transducin can accomplish this task itself by converting --hydrolyzing -- its bound GTP molecule into guanosine diphosphate, GDP. (This conversion from GTP to GDP is a commonly used molecular "switch" in a variety of cellular signalling pathways.) Because transducin bound to GDP has a low affinity for phosphodiesterase, it releases the enzyme in an inactive form, allowing cGMP levels to rise again and return the flow of ions across the cell membrane to the "dark" state. In this molecular cascade, then, the conversion of GTP to GDP by transducin is the rate-limiting step that defines the amount of time for which a photoreceptor responds to a light pulse.
4) But this presents a problem. Photoreceptor cells can turn off in less than a second in response to a brief flash of light(2). In contrast, the hydrolysis of GTP by transducin requires tens of seconds to complete, making it difficult to understand how such a mechanism could account for the rapid turn-off of photoreceptor cells. To get around this problem, photoreceptor cells possess a protein called regulator of G-protein signalling-9 (RGS9) that accelerates transducin's ability to hydrolyze GTP3. Indeed, mice that lack the RGS9 gene exhibit slow photoreceptor deactivation(4,5).
References (abridged):
1. Nishiguchi, K. M. et al. Nature 427, 75-78 (2004)
2. Arshavsky, V. Y., Lamb, T. D. & Pugh, E. N. Jr Annu. Rev. Physiol. 64, 153-187 (2002)
3. He, W., Cowan, C. W. & Wensel, T. G. Neuron 20, 95-102 (1998)
4. Chen, C. K. et al. Nature 403, 557-560 (2000)
5. Kooijman, A. C., Houtman, A., Damhof, A. & van Engelen, J. P. Doc. Ophthalmol. 78, 245-254 (1991)
Nature http://www.nature.com/nature
--------------------------------
ON NEURAL OPTIMIZATION OF RETINAL INPUTS
The following points are made by Martin Wilson (Current Biology 2002 12:R625):
1) Every neuron in the brain faces the task of discriminating useful incoming signals from a background of useless noise. Much of this noise is inevitable in any miniaturized device and comes from the stochastic behavior of the signaling molecules from which neurons are constructed. In a recent study, Field and Rieke [1] have taken a reverse engineering approach to an early step in vision to examine how this is done; they find, counterintuitively, that to optimize performance much of the signal is thrown out with the noise.
2) Because light arrives as discrete quanta, the problem of seeing in very low light conditions is essentially that of signaling the capture of enough photons for reliable statistical estimates about the relative brightness of different parts of the visible world. Mammals, particularly nocturnal mammals, have retinas with large numbers of rod photoreceptors dedicated to low light vision. Each rod is a very high gain detector with 10 million copies of a light-capturing molecule, rhodopsin, coupled to a multistage biochemical amplifier. When a photon is absorbed by one rhodopsin molecule, activation of the biochemical amplifier results in the closure of cation channels in the plasma membrane, giving rise to a current blip lasting about one second and about one picoamp in amplitude.
2) The consequent small voltage signal is propagated to the axon terminal, where it is passed on to the next layer of cells, the bipolar cells, through three different pathways. "OFF" bipolar cells, which signal a light increase with hyperpolarization, receive rod signals in two ways: first, via a recently discovered direct synaptic connection between rods and OFF bipolar cells; and second, indirectly via rod cone electrical coupling and cone synapses. The most prominent pathway, however, is a direct synaptic connection between rods and a type of ON bipolar cell, the rod bipolar cell, that draws input exclusively from rods and is thought to be part of a special pathway used for vision in the dimmest environments.
3) Dozens or even hundreds of rods are synaptically wired to every rod bipolar cell. This makes engineering sense, as only by pooling the scarce photon signals is it possible for the visual system to make statistically reliable discriminations. Convergence brings a problem, however, as the high gain of rods results in their being noisy, even in darkness. A particularly troublesome kind of noise is a continuous fluctuation in the current stemming from the instability of the phosphodiesterase molecules that form an intermediate stage in the rod's biochemical amplifier [2] . This kind of noise would swamp the signal in a bipolar cell at the very dimmest intensities, where no more than one rod is likely to contribute signal but every rod contributes noise. One trick often used by the nervous system to remove noise is to filter out the temporal frequencies unique to the noise, thereby leaving mostly signal. This strategy seems to be used at the rod-to-rod bipolar cell synapse [3] , but unfortunately the temporal frequencies of signal and noise overlap too much for this to be enough. Nevertheless, as Field and Rieke [1] have shown, noise can be optimally filtered out solely on the basis of the amplitude distributions of signal and noise [4,5].
References (abridged):
1. Field G.D. and Rieke F. (2002) Nonlinear signal transfer from mouse rods to bipolar cells and implications for visual sensitivity. Neuron, 34:773-785.
2. Rieke F. and Baylor D.A. (1996) Molecular origin of continuous dark noise in rod photoreceptors. Biophys. J., 71:2553-2572.
3. Bialek W. and Owen W.G. (1990) Temporal filtering in retinal bipolar cells. Elements of an optimal computation? Biophys. J., 58:1227-1233.
4. Rieke F. and Baylor D.A. (1998) Single-photon detection by rod cells of the retina. Rev. Mod. Phys., 70:1027-1036.
5. Euler T. and Masland R.H. (2000) Light-evoked responses of bipolar cells in a mammalian retina. J. Neurophysiol., 83:1817-1829.
--------------------------------
NONLINEAR SIGNAL TRANSFER FROM MOUSE RODS TO BIPOLAR CELLS AND IMPLICATIONS FOR VISUAL SENSITIVITY
The following points are made by G.D. Field and R. Rieke (Neuron 2002 34:773):
1) The authors report they investigated the impact of rod-bipolar signal transfer on visual sensitivity. Two observations indicate that rod-rod bipolar signal transfer is nonlinear. First, responses of rods increased linearly with flash strength, while those of rod bipolars increased supralinearly. Second, fluctuations in the responses of rod bipolars were larger than expected from linear summation of the rod inputs. Rod-OFF bipolar signal transfer did not share this strong nonlinearity.
2) Surprisingly, nonlinear rod-rod bipolar signal transfer eliminated many of the rod's single-photon responses. The impact on sensitivity, however, was more than compensated for by rejection of noise from rods that did not absorb photons. As a consequence, rod bipolars provide a near-optimal readout of rod signals at light levels near visual threshold.
Neuron http://www.neuron.org
--------------------------------
MOLECULAR ORIGIN OF CONTINUOUS DARK NOISE IN ROD PHOTORECEPTORS
The following points are made by F. Rieke and D.A. Baylor (Biophys J 1996 71:2553):
1) Noise in the rod photoreceptors limits the ability of the dark-adapted visual system to detect dim lights. The authors report they investigated the molecular mechanism of the continuous component of the electrical dark noise in toad rods. Membrane current was recorded from intact, isolated rods or truncated, internally dialyzed rod outer segments. The continuous noise was separated from noise due to thermal activation of rhodopsin and to transitions in the cGMP-activated channels. Selectively disabling different elements of the phototransduction cascade allowed examination of their contributions to the continuous noise.
2) The authors suggest these experiments indicate that the noise is generated by spontaneous activation of cGMP phosphodiesterase (PDE) through a process that does not involve transducin. The addition of recombinant gamma, the inhibitory subunit of PDE, did not suppress the noise, indicating that endogenous gamma does not completely dissociate from the catalytic subunit of PDE during spontaneous activation. Quantitative analysis of the noise provided estimates of the rate constants for spontaneous PDE activation and deactivation and the catalytic activity of a single PDE molecule in situ.
Biophysical J. http://www.biophysj.org
--------------------------------
TEMPORAL FILTERING IN RETINAL BIPOLAR CELLS. ELEMENTS OF AN OPTIMAL COMPUTATION?
The following points are made by W. Bialek and W.G.Owen (Biophys J 1990 58:1227):
1) Recent experiments indicate that the dark-adapted vertebrate visual system can count photons with a reliability limited by dark noise in the rod photoreceptors themselves. This suggests that subsequent layers of the retina, responsible for signal processing, add little if any excess noise and extract all the available information. Given the signal and noise characteristics of the photoreceptors, what is the structure of such an optimal processor?
2) The authors demonstrate that optimal estimates of time-varying light intensity can be accomplished by a two-stage filter, and the authors suggest that the first stage should be identified with the filtering which occurs at the first anatomical stage in retinal signal processing, signal transfer from the rod photoreceptor to the bipolar cell. This leads to parameter-free predictions of the bipolar cell response, which are in excellent agreement with experiments comparing rod and bipolar cell dynamics in the same retina.
3) The authors suggest this is the first case in which the computationally significant dynamics of a neuron could be predicted rather than modeled.
Biophysical J. http://www.biophysj.org
ScienceWeek http://scienceweek.com
|