Synaptic Ca2+ in Darkness Is Lower in Rods than Cones, Causing Slower Tonic Release of Vesicles

Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2007; 27(19):5033-42. DOI: 10.1523/JNEUROSCI.5386-06.2007
Source: PubMed


Rod and cone photoreceptors use specialized biochemistry to generate light responses that differ in their sensitivity and kinetics. However, it is unclear whether there are also synaptic differences that affect the transmission of visual information. Here, we report that in the dark, rods tonically release synaptic vesicles at a much slower rate than cones, as measured by the release of the fluorescent vesicle indicator FM1-43. To determine whether slower release results from a lower Ca2+ sensitivity or a lower dark concentration of Ca2+, we imaged fluorescent indicators of synaptic vesicle cycling and intraterminal Ca2+. We report that the Ca2+ sensitivity of release is indistinguishable in rods and cones, consistent with their possessing similar release machinery. However, the dark intraterminal Ca2+ concentration is lower in rods than in cones, as determined by two-photon Ca2+ imaging. The lower level of dark Ca2+ ensures that rods encode intensity with a slower vesicle release rate that is better matched to the lower information content of dim light.

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    • "Other factors such as vesicle descent down the ribbon may contribute to slower kinetics of replenishment, but if vesicle delivery to the ribbon is the rate-limiting step in replenishment, then this suggests that the probability of a single vesicle attaching to the ribbon upon collision is likely to be significantly <1. Although we used vesicle density measurements from salamander cones (Sheng et al., 2007), vesicles appear less concentrated in mouse rod terminals, 580–750 v/µm 3 (Zampighi et al., 2011), implying there may be cell-tocell or species-to-species differences in the kinetics of vesicle resupply. We developed two variations of the model to test possible sites of Ca 2+ /CaM regulation of replenishment. "
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    ABSTRACT: At the first synapse in the vertebrate visual pathway, light-evoked changes in photoreceptor membrane potential alter the rate of glutamate release onto second-order retinal neurons. This process depends on the synaptic ribbon, a specialized structure found at various sensory synapses, to provide a supply of primed vesicles for release. Calcium (Ca(2+)) accelerates the replenishment of vesicles at cone ribbon synapses, but the mechanisms underlying this acceleration and its functional implications for vision are unknown. We studied vesicle replenishment using paired whole-cell recordings of cones and postsynaptic neurons in tiger salamander retinas and found that it involves two kinetic mechanisms, the faster of which was diminished by calmodulin (CaM) inhibitors. We developed an analytical model that can be applied to both conventional and ribbon synapses and showed that vesicle resupply is limited by a simple time constant, τ = 1/(Dρδs), where D is the vesicle diffusion coefficient, δ is the vesicle diameter, ρ is the vesicle density, and s is the probability of vesicle attachment. The combination of electrophysiological measurements, modeling, and total internal reflection fluorescence microscopy of single synaptic vesicles suggested that CaM speeds replenishment by enhancing vesicle attachment to the ribbon. Using electroretinogram and whole-cell recordings of light responses, we found that enhanced replenishment improves the ability of cone synapses to signal darkness after brief flashes of light and enhances the amplitude of responses to higher-frequency stimuli. By accelerating the resupply of vesicles to the ribbon, CaM extends the temporal range of synaptic transmission, allowing cones to transmit higher-frequency visual information to downstream neurons. Thus, the ability of the visual system to encode time-varying stimuli is shaped by the dynamics of vesicle replenishment at photoreceptor synaptic ribbons.
    The Journal of General Physiology 10/2014; 144(5). DOI:10.1085/jgp.201411229 · 4.79 Impact Factor
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    • "Are there differences in adaptative signaling in cone and rod synapses and eventually also between the different active zones present in cone synapses? Recent Ca 2+ -imaging analyses strongly argue that this is the case (Johnson et al., 2007; Sheng et al., 2007). Most of our current knowledge about the physiology of retinal ribbon synapses was obtained from goldfish bipolar cells and salamander photoreceptors. "
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    ABSTRACT: Photoreceptors, the light-sensitive receptor neurons of the retina, receive and transmit a plethora of visual informations from the surrounding world. Photoreceptors capture light and convert this energy into electrical signals that are conveyed to the inner retina. For synaptic communication with the inner retina, photoreceptors make large active zones that are marked by synaptic ribbons. These unique synapses support continuous vesicle exocytosis that is modulated by light-induced, graded changes of membrane potential. Synaptic transmission can be adjusted in an activity-dependent manner, and at the synaptic ribbons, Ca(2+)- and cGMP-dependent processes appear to play a central role. EF-hand-containing proteins mediate many of these Ca(2+)- and cGMP-dependent functions. Since continuous signaling of photoreceptors appears to be prone to malfunction, disturbances of Ca(2+)- and cGMP-mediated signaling in photoreceptors can lead to visual defects, retinal degeneration (rd), and even blindness. This review summarizes aspects of signal transmission at the photoreceptor presynaptic terminals that involve EF-hand-containing Ca(2+)-binding proteins.
    Frontiers in Molecular Neuroscience 02/2012; 5:26. DOI:10.3389/fnmol.2012.00026 · 4.08 Impact Factor
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    • "The identity of the calcium sensor molecules that regulate exocytosis from photoreceptors is unclear. Experiments on nonmammalian rods and cones show that the sensor exhibits an unusually high affinity for Ca 2+ with a threshold of 400 nM and low cooperativity of approximately two Ca 2+ ions (Rieke & Schwartz, 1996; Thoreson et al., 2004; Sheng et al., 2007; Duncan et al., 2010). This is quite different from release at synapses employing synaptotagmin 1, which show a cooperativity of five Ca 2+ ions and a requirement for much higher Ca 2+ levels (Heidelberger et al., 1994; Bollmann et al., 2000; Schneggenburger & Neher, 2000; Beutner et al., 2001). "
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    ABSTRACT: Rod and cone photoreceptors possess ribbon synapses that assist in the transmission of graded light responses to second-order bipolar and horizontal cells of the vertebrate retina. Proper functioning of the synapse requires the juxtaposition of presynaptic release sites immediately adjacent to postsynaptic receptors. In this review, we focus on the synaptic, cytoskeletal, and extracellular matrix proteins that help to organize photoreceptor ribbon synapses in the outer plexiform layer. We examine the proteins that foster the clustering of release proteins, calcium channels, and synaptic vesicles in the presynaptic terminals of photoreceptors adjacent to their postsynaptic contacts. Although many proteins interact with one another in the presynaptic terminal and synaptic cleft, these protein-protein interactions do not create a static and immutable structure. Instead, photoreceptor ribbon synapses are remarkably dynamic, exhibiting structural changes on both rapid and slow time scales.
    Visual Neuroscience 11/2011; 28(6):453-71. DOI:10.1017/S0952523811000356 · 2.21 Impact Factor
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