The brain computes visual colour by analysing the relative excitations of three types of retinal cones. Each cone excitation is governed by a spectral sensitivity function which relates the amplitude of the neural response to wavelength at constant light intensity. The spectral sensitivities of human cones are not well characterized. We report measuring the sensitivities by recording electrical responses of human cones to stimuli of different wavelengths. Spectral sensitivities of 'green' and 'red' cones, determined over the entire visible region, show peaks near 530 and 560 nm respectively, and are remarkably similar to those of the old-world monkey Macaca fascicularis. They satisfactorily predict the photopic luminosity function, a measure of the sensitivity of cone-mediated human vision to light of different wavelengths. The kinetics of the light responses of human cones also appeared similar to those of macaque cones: the time to peak response to a dim flash was 50-100 ms and there was a characteristic undershoot during recovery.
OPs have been used to evaluate retinal function in both diabetic models and patients. The comparison of amplitude-matched OPs is a robust determinant of changes in kinetics. Researchers and clinicians who use OPs may wish to consider the relationship between OP amplitude and kinetics to avoid confounding assessments of abnormalities. The amplitude versus kinetics relationship does not change form in diabetic animals; it is merely shifted (delayed) on the time axis.
SUMMARY1. Photocurrents were recorded with suction electrodes from rod photoreceptors of seven humans.2. Brief flashes of light evoked transient outward currents of up to 20 pA. With increasing light intensity the peak response amplitude increased along an exponential saturation function. A half-saturating peak response was evoked by approximately sixty-five photoisomerizations.3. Responses to brief dim flashes rose to a peak in about 200 ms. The waveform was roughly like the impulse response of a series of four to five low-pass filters.4. The rising phases of the responses to flashes of increasing strength were found to fit with a biochemical model of phototransduction with an 'effective delay time' and 'characteristic time' of about 2 and 800 ms, respectively.5. Spectral sensitivities were obtained over a wavelength range from 380 to 760 nm. The action spectrum, which peaked at 495 nm, followed the template described for photoreceptors in the macaque retina. Variation between rods in the position of the spectrum on the wavelength axis was small.6. The scotopic luminosity function derived from human psychophysical experiments was found to agree well with the measured rod action spectrum after adjustments were made for lens absorption and photopigment self-screening in the intact eye.7. Responses to steps of light rose monotonically to a maintained level, showing little or no relaxation. Nevertheless, the relationship between light intensity and steady-state response amplitude was shallower than that expected from simple response saturation. This is consistent with an adaptation mechanism acting on a rapid time scale.8. Flash sensitivity fell with increasing intensities of background light according to Weber's law. Sensitivity was reduced twofold by lights evoking about 120 photoisomerizations per second. Background lights decreased the time to peak and the integration time of the flash response by up to 20%.
Vertebrate cone and rod photoreceptor cells use similar mechanisms to transduce light signals into electrical signals, but their responses to light differ in sensitivity and kinetics. To assess the role of G-protein GTP hydrolysis kinetics in mammalian cone photoresponses, we have characterized photoresponses and GTPase regulatory components of cones and rods from the cone-dominant retina of the eastern chipmunk. Sensitivity, based on the stimulus strength required for a half-maximum response, of the M-cone population was 38-fold lower than that of the rods. The relatively lower cone sensitivity could be attributed in part to lower amplification in the rising phase and in part to faster recovery kinetics. At a molecular level, cloning of chipmunk cDNA and expression of recombinant proteins provided standards for quantitative immunoblot analysis of proteins involved in GTPase acceleration. The ratio of the cGMP-phosphodiesterase inhibitory subunit gamma to cone pigment, 1:68, was similar to the levels observed for ratios to rhodopsin in bovine retina, 1:76, or mouse retina, 1:65. In contrast, the ratio to pigment of the GTPase-accelerating protein RGS9-1 was 1:62, more than 10 times higher than ratios observed in rod-dominant retinas. Immunoprecipitation experiments revealed that, in contrast to rods, RGS9-1 in chipmunk retina is associated with both the short and long isoforms of its partner subunit G(beta5). The much higher levels of the GTPase-accelerating protein complex in cones, compared with rods, suggest a role for GTPase acceleration in obtaining rapid photoresponse kinetics.
Ion flow into the rod photoreceptor outer segment (ROS) is regulated by a member of the cyclic-nucleotide-gated cation-channel family; this channel consists of two subunit types, α and β. In the rod cells, the Cngb1 locus encodes the channel β-subunit and two related glutamic-acid-rich proteins (GARPs). Despite intensive research, it is still unclear why the β-subunit and GARPs are coexpressed and what function these proteins serve. We hypothesized a role for the proteins in the maintenance of ROS structural integrity. To test this hypothesis, we created a Cngb1 5′-knockout photoreceptor null (Cngb1-X1). Morphologically, ROSs were shorter and, in most rods that were examined, some disks were misaligned, misshapen and abnormally elongated at periods when stratification was still apparent and degeneration was limited. Additionally, a marked reduction in the level of channel α-subunit, guanylate cyclase I (GC1) and ATP-binding cassette transporter (ABCA4) was observed without affecting levels of other ROS proteins, consistent with a requirement for the β-subunit in channel assembly or targeting of select proteins to ROS. Remarkably, phototransduction still occurred when only trace levels of homomeric α-subunit channels were present, although rod sensitivity and response amplitude were both substantially reduced. Our results demonstrate that the β-subunit and GARPs are necessary not only to maintain ROS structural integrity but also for normal disk morphogenesis, and that the β-subunit is required for normal light sensitivity of the rods.
Ward et al. report retinal thinning in humans with progranulin mutations that precedes dementia onset, and an age-dependent retinal neurodegenerative phenotype in progranulin null mice. Nuclear depletion of TDP-43 precedes retinal neuronal loss and is accompanied by reduced GTPase Ran, with overexpression of Ran restoring nuclear TDP-43 and neuronal survival.
SUMMARY1. Visual transduction in photoreceptors of the ground squirrel, Citellus lateralis, was studied by recording membrane current from individual cones in small pieces of retina.2. Brief flashes of light produced transient reductions of the dark current; saturating response amplitudes were up to 67 pA. A flash strength of about 11000 photons /tm-2 at A,,. was required to give a half-saturating response. The stimulusresponse relation was well fitted by an exponential saturation curve. Responses below 20% of maximum behaved linearly.3. The response to a dim flash in most cells had a time to peak of 20-30 ms and resembled the impulse response of a series of five low-pass filters.4. The variance of the dim-flash response amplitude put an upper limit of 80 fA on the size of the single photon response. Estimates based on the effective collecting area suggest the single photon response to be of the order of 10 fA.5. Flash responses of squirrel cones usually lacked the undershoot observed in primate cones, although in about I of the cells a small undershoot developed during recording.6. Background lights slightly shortened the time to peak of the flash response and reduced the integration time. 7. Spectral sensitivity measurements showed two classes of cones with peak sensitivities at about 520 and 435 nm. Rod sensitivity peaked near 500 nm. Spectral univariance was obeyed by all three classes of cells.8. The shapes of the spectral sensitivity curves of the rod and both types of cones were similar to each other when plotted on a log wave number scale, but differed significantly from similar plots of monkey and human cone spectra.9. The kinetics and sensitivity of flash responses of the blue-and green-sensitive cones were indistinguishable.
It has been known for decades that neurons throughout the brain possess solitary, immotile, microtubule based appendages called primary cilia. Only recently have studies tried to address the functions of these cilia and our current understanding remains poor. To determine if neuronal cilia have a role in behavior we specifically disrupted ciliogenesis in the cortex and hippocampus of mice through conditional deletion of the Intraflagellar Transport 88 (Ift88) gene. The effects on learning and memory were analyzed using both Morris Water Maze and fear conditioning paradigms. In comparison to wild type controls, cilia mutants displayed deficits in aversive learning and memory and novel object recognition. Furthermore, hippocampal neurons from mutants displayed an altered paired-pulse response, suggesting that loss of IFT88 can alter synaptic properties. A variety of other behavioral tests showed no significant differences between conditional cilia mutants and controls. This type of conditional allele approach could be used to distinguish which behavioral features of ciliopathies arise due to defects in neural development and which result from altered cell physiology. Ultimately, this could lead to an improved understanding of the basis for the cognitive deficits associated with human cilia disorders such as Bardet-Biedl syndrome, and possibly more common ailments including depression and schizophrenia.
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