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Peter Sterling

Publications and source records attributed to Peter Sterling.

At least 19 recordsLinked to original sources
PubMed2005

Structure and function of ribbon synapses.

Sensory neurons with short conduction distances can use nonregenerative, graded potentials to modulate transmitter release continuously. This mechanism can transmit information at much higher rates than spiking. Graded signaling requires a synapse to sustain high rates of exocytosis for relatively long periods, and this capacity is the special virtue of ribbon synapses. Vesicles tethered to the ribbon provide a pool for sustained release that is typically fivefold greater than the docked pool available for fast release. The current article, which is part of the TINS Synaptic Connectivity series, reviews recent evidence for this fundamental computational strategy and its underlying cell biology.

Action Potentials↗
PubMed2004

Sluggish and brisk ganglion cells detect contrast with similar sensitivity.

Roughly half of all ganglion cells in mammalian retina belong to the broad class, termed "sluggish." Many of these cells have small receptive fields and project via lateral geniculate nuclei to visual cortex. However, their possible contributions to perception have been largely ignored because sluggish cells seem to respond weakly compared with the more easily studied "brisk" cells. By selecting small somas under infrared DIC optics and recording with a loose seal, we could routinely isolate sluggish cells. When a spot was matched spatially and temporally to the receptive field center, most sluggish cells could detect the same low contrasts as brisk cells. Detection thresholds for the two groups determined by an "ideal observer" were similar: threshold contrast for sluggish cells was 4.7 +/- 0.5% (mean +/- SE), and for brisk cells was 3.4 +/- 0.3% (Mann-Whitney test: P > 0.05). Signal-to-noise ratios for the two classes were also similar at low contrast. However, sluggish cells saturated at somewhat lower contrasts (contrast for half-maximum response was 14 +/- 1 vs. 19 +/- 2% for brisk cells) and were less sensitive to higher temporal frequencies (when the stimulus frequency was increased from 2 to 4 Hz, the response rate fell by 1.6-fold). Thus the sluggish cells covered a narrower dynamic range and a narrower temporal bandwidth, consistent with their reported lower information rates. Because information per spike is greater at lower firing rates, sluggish cells may represent "cheaper" channels that convey less urgent visual information at a lower energy cost.

Action Potentials↗
PubMed2004

Visualizing synaptic ribbons in the living cell.

Visual and auditory information is encoded by sensory neurons that tonically release neurotransmitter at high rates. The synaptic ribbon is an essential organelle in nerve terminals of these neurons. Its precise function is unknown, but if the ribbon could be visualized in a living terminal, both its own dynamics and its relation to calcium and vesicle dynamics could be studied. We designed a short fluorescent peptide with affinity for a known binding domain of RIBEYE, a protein unique to the ribbon. When introduced via a whole-cell patch pipette, the peptide labeled structures at the presynaptic plasma membrane of ribbon-type terminals. The fluorescent spots match in size, location, number, and distribution the known features of synaptic ribbons. Furthermore, fluorescent spots mapped by confocal microscopy directly match the ribbons identified by electron microscopy in the same cell. Clearly the peptide binds to the synaptic ribbon, but even at saturating concentrations it affects neither the morphology of the ribbon nor its tethering of synaptic vesicles. It also does not inhibit exocytosis. Using the peptide label, we observed that the ribbon is immobile over minutes and that calcium influx is concentrated at the ribbon. Finally, we find that each ribbon in a retinal bipolar cell contains approximately 4000 molecules of RIBEYE, indicating that it is the major component of the synaptic ribbon.

Amino Acid Motifs↗
PubMed2004

Evidence that certain retinal bipolar cells use both glutamate and GABA.

Retinal bipolar neurons release the excitatory transmitter, glutamate. However, certain bipolar cells contain GABA, raising the question whether a neuron might release both transmitters and, if so, what function might the inhibitory transmitter play in a particular circuit? Here we identify a subset of cone bipolar cells in cat retina that contain glutamate, plus its vesicular transporter (VGLUT1), and GABA, plus its synthetic enzyme (GAD(65)) and its vesicular transporter (VGAT). These cells are negative for a marker of ON bipolar cells and restrict their axons to the OFF strata of the inner synaptic layer. They do not colocalize with the neurokinin 3 receptor that stains a type (or two) of OFF bipolar cells. By "targeted injection," we identified two types of OFF bipolar cell with the machinery to make and package both transmitters. One of these types costratifies with a dopamine plexus.

Animals↗
PubMed2004

Evidence that each S cone in macaque fovea drives one narrow-field and several wide-field blue-yellow ganglion cells.

A rule of retinal wiring is that many receptors converge onto fewer bipolar cells and still fewer ganglion cells. However, for each S cone in macaque fovea, there are two S-cone ON bipolar cells and two blue-yellow (BY) ganglion cells. To understand this apparent rule reversal, we reconstructed synaptic patterns of divergence and convergence and determined the basic three-tiered unit of connectivity that repeats across the retina. Each foveal S cone diverges to four S-cone ON bipolar cells but contacts them unequally, providing 1-16 ribbon synapses per cell. Next, each bipolar cell diverges to two BY ganglion cells and also contacts them unequally, providing approximately 14 and approximately 28 ribbon synapses per cell. Overall, each S cone diverges to approximately six BY ganglion cells, dominating one and contributing more modestly to the others. Conversely, of each pair of BY ganglion cells, one is dominated by a single S cone and one is diffusely driven by several. This repeating circuit extracts blue/yellow information on two different spatiotemporal scales and thus parallels the circuits for achromatic, spatial vision, in which each cone dominates one narrow-field ganglion cell (midget) and contributes some input to several wider-field ganglion cells (parasol). Finally, because BY ganglion cells have coextensive +S and -(L+M) receptive fields, and each S cone contributes different weights to different BY ganglion cells, the coextensive receptive fields must be already present in the synaptic terminal of the S cone. The S-cone terminal thus constitutes the first critical locus for BY color vision.

Animals↗
PubMed2004

Efficiency of information transmission by retinal ganglion cells.

BACKGROUND: Different types of retinal ganglion cells convey different messages to the brain. Messages are in the form of spike patterns, and the number of possible patterns per second sets the coding capacity. We asked if different ganglion cell types make equally efficient use of their coding capacity or whether efficiency depends on the message conveyed. RESULTS: We recorded spike trains from retinal ganglion cells in an in vitro preparation of the guinea pig retina. By calculating, for the observed spike rate, the number of possible spike patterns per second, we calculated coding capacity, and by counting the actual number of patterns, we estimated information rate. Cells with "brisk" responses, i.e., high firing rates, and a general message transmitted information at high rates (21 +/- 9 bits s(-1)). Cells with "sluggish" responses, i.e., lower firing rates, and specific messages (direction of motion, local-edge) transmitted information at lower rates (13 +/- 7 bits s(-1)). Yet, for every type of ganglion cell examined, the information rate was about one-third of coding capacity. For every ganglion cell, information rate was very close (within 4%) to that predicted from Poisson noise and the cell's actual time-modulated rate. CONCLUSIONS: Different messages are transmitted with similar efficiency. Efficiency is limited by temporal correlations, but correlations may be essential to improve decoding in the presence of irreducible noise.

Action Potentials↗
PubMed2004

A retinal-specific regulator of G-protein signaling interacts with Galpha(o) and accelerates an expressed metabotropic glutamate receptor 6 cascade.

G(o) is the most abundant G-protein in the brain, but its regulators are essentially unknown. In retina, Galpha(o1) is obligatory in mediating the metabotropic glutamate receptor 6 (mGluR6)-initiated ON response. To identify the interactors of G(o), we conducted a yeast two-hybrid screen with constituitively active Galpha(o) as a bait. The screen frequently identified a regulator of G-protein signaling (RGS), Ret-RGS1, the interaction of which we confirmed by coimmunoprecipitation with Galpha(o) in transfected cells and in retina. Ret-RGS1 localized to the dendritic tips of ON bipolar neurons, along with mGluR6 and Galpha(o1). When Ret-RGS1 was coexpressed in Xenopus oocytes with mGluR6, Galpha(o1), and a GIRK (G-protein-gated inwardly rectifying K+) channel, it accelerated the deactivation of the channel response to glutamate in a concentration-dependent manner. Because light onset suppresses glutamate release from photoreceptors onto the ON bipolar dendrites, Ret-RGS1 should accelerate the rising phase of the light response of the ON bipolar cell. This would tend to match its kinetics to that of the OFF bipolar that arises directly from ligand-gated channels.

Animals↗
PubMed2004

How retinal ganglion cells prevent synaptic noise from reaching the spike output.

Synaptic vesicles are released stochastically, and therefore stimuli that increase a neuron's synaptic input might increase noise at its spike output. Indeed this appears true for neurons in primary visual cortex, where spike output variability increases with stimulus contrast. But in retinal ganglion cells, although intracellular recordings (with spikes blocked) showed that stronger stimuli increase membrane fluctuations, extracellular recordings showed that noise at the spike output is constant. Here we show that these seemingly paradoxical findings occur in the same cell and explain why. We made intracellular recordings from ganglion cells, in vitro, and presented periodic stimuli of various contrasts. For each stimulus cycle, we measured the response at the stimulus frequency (F1) for both membrane potential and spikes as well as the spike rate. The membrane and spike F1 response increased with contrast, but noise (SD) in the F1 responses and the spike rate was constant. We also measured membrane fluctuations (with spikes blocked) during the response depolarization and found that they did increase with contrast. However, increases in fluctuation amplitude were small relative to the depolarization (<10% at high contrast). A model based on estimated synaptic convergence, release rates, and membrane properties accounted for the relative magnitudes of fluctuations and depolarization. Furthermore, a cell's peak spike response preceded the peak depolarization, and therefore fluctuation amplitude peaked as the spike response declined. We conclude that two extremely general properties of a neuron, synaptic convergence and spike generation, combine to minimize the effects of membrane fluctuations on spiking.

Anesthetics, Local↗
PubMed2004

Streamlined synaptic vesicle cycle in cone photoreceptor terminals.

Cone photoreceptors tonically release neurotransmitter in the dark through a continuous cycle of exocytosis and endocytosis. Here, using the synaptic vesicle marker FM1-43, we elucidate specialized features of the vesicle cycle. Unlike retinal bipolar cell terminals, where stimulation triggers bulk membrane retrieval, cone terminals appear to exclusively endocytose small vesicles. These retain their integrity until exocytosis, without pooling their membranes in endosomes. Endocytosed vesicles rapidly disperse through the terminal and are reused with no apparent delay. Unlike other synapses where most vesicles are immobilized and held in reserve, only a small fraction (<15%) becomes immobilized in cones. Photobleaching experiments suggest that vesicles move by diffusion and not by molecular motors on the cytoskeleton and that vesicle movement is not rate limiting for release. The huge reservoir of vesicles that move rapidly throughout cone terminals and the lack of a reserve pool are unique features, providing cones with a steady supply for continuous release.

Animals↗
PubMed2004

Design for a binary synapse.

The mammalian rod transfers a binary signal, the capture of 0 or 1 photon. In this issue of Neuron, Sampath and Rieke show in mouse that the rod's tonic exocytosis in darkness completely saturates a G protein cascade to close nearly all postsynaptic channels. A full-sized photon event supresses exocytosis sufficiently to allow approximately 30 postsynaptic channels to open simultaneously. Thus, the synapse behaves like a digital gate, whose hallmark is reliability and resistance to noise.

Animals↗
PubMed2003

Macaque retina contains an S-cone OFF midget pathway.

Psychophysical results suggest that the primate visual system is equally sensitive to both the onset and offset of short-wavelength light and that these responses are carried by separate pathways. However, physiological studies of cells in the retina and lateral geniculate nucleus find far fewer OFF-center than ON-center cells whose receptive-field centers are driven by short-wavelength-sensitive (S) cones. To determine whether S cones contact ON and OFF midget bipolar cells as well as (ON) "blue-cone bipolar" cells (Mariani, 1984), we examined 118 contiguous cone terminals and their bipolar cells in electron micrographs of serial sections from macaque foveal retina. Five widely spaced cone terminals do not contact ON midget bipolar cells. These five cone terminals contact the dendrites of "blue-cone bipolar" cells instead, showing that they are the terminals of S cones. These S-cone terminals are smaller and contain more synaptic ribbons than other terminals. Like neighboring cones, each S cone contacts its own OFF midget bipolar cell via triad-associated (flat) synaptic contacts. Moreover, each S-cone OFF midget bipolar cell has a synaptic terminal in the outer half of the inner plexiform layer, where it contacts an OFF midget ganglion cell.

Animals↗
PubMed2003

Endocytosis and vesicle recycling at a ribbon synapse.

At ribbon synapses, where exocytosis is regulated by graded depolarization, vesicles can fuse very rapidly with the plasma membrane (complete discharge of the releasable pool in approximately 200 msec). Vesicles are also retrieved very rapidly (time constant of approximately 1 sec), leading us to wonder whether their retrieval uses an unusual mechanism. To study this, we exposed isolated bipolar neurons from goldfish retina to cationized ferritin. This electron-dense marker uniformly decorated the cell membrane and was carried into the cell during membrane retrieval. Endocytosis was activity-dependent and restricted to the synaptic terminal. The labeling pattern was consistent with direct retrieval from the plasma membrane of large, uncoated endosomes 60-200 nm in diameter. Even after extensive synaptic activity lasting several minutes, most of the ferritin remained in large endosomes and was present in only approximately 10% of the small vesicles that constitute the reserve pool. By contrast, after brief stimulation at a conventional terminal, ferritin did not reside in endosomes but was present in approximately 63% of the small vesicles. We suggest that the bipolar ribbon synapse sustains its rapid exocytosis by retrieving membrane in larger "bites" than the clathrin-dependent mechanism thought to dominate at conventional synapses. The resulting large endosomes bud off small vesicles, which reenter the reserve pool and finally the releasable pool.

Action Potentials↗
PubMed2003

Timing of quantal release from the retinal bipolar terminal is regulated by a feedback circuit.

In isolation, a presynaptic terminal generally releases quanta according to Poisson statistics, but in a circuit its release statistics might be shaped by synaptic interactions. We monitored quantal glutamate release from retinal bipolar cell terminals (which receive GABA-ergic feedback from amacrine cells) by recording spontaneous EPSCs (sEPSCs) in their postsynaptic amacrine and ganglion cells. In about one-third of these cells, sEPSCs were temporally correlated, arriving in brief bursts (10-55 ms) more often than expected from a Poisson process. Correlations were suppressed by antagonizing the GABA(C) receptor (expressed on bipolar terminals), and correlations were induced by raising extracellular calcium or osmolarity. Simulations of the feedback circuit produced "bursty" release when the bipolar cell escaped intermittently from inhibition. Correlations of similar duration were present in the light-evoked sEPSCs and spike trains of sluggish-type ganglion cells. These correlations were suppressed by antagonizing GABA(C) receptors, indicating that glutamate bursts from bipolar terminals induce spike bursts in ganglion cells.

Action Potentials↗
PubMed2003

Inner S-cone bipolar cells provide all of the central elements for S cones in macaque retina.

Synaptic terminals of cones (pedicles) are presynaptic to numerous processes that arise from the dendrites of many types of bipolar cell. One kind of process, a central element, reaches deeply into invaginations of the cone pedicle just below an active zone associated with a synaptic ribbon. By reconstruction from serial electron micrographs, we show that L- and M-cone pedicles in macaque fovea are presynaptic to approximately 20 central elements that arise from two types of inner (invaginating) bipolar cell, midget and diffuse. In contrast, S-cone pedicles, with more synaptic ribbons, active zones/ribbon, and central elements/active zone, are presynaptic to approximately 33 central elements. Moreover, all of these arise from one type of bipolar cell, previously described by others, here termed an inner S-cone bipolar cell. Each provides approximately 16 central elements. Thirty-three is twice 16; correspondingly, these bipolar cells are twice as numerous as S cones. (Specifically, each S cone is presynaptic to four inner S-cone bipolar cells; in turn, each bipolar cell provides central elements to two S cones.) These bipolar cells are presynaptic to an equal number of small-field bistratified ganglion cells, giving cell numbers in 2G:2B:1S ratios. Each ganglion cell receives input from two or more inner S-cone bipolar cells and thereby collects signals from three or more S cones. This convergence, along with chromatic aberration of short-wavelength light, suggests that S-cone contributions to this ganglion cell's coextensive blue-ON/yellow-OFF receptive field are larger than opponent L/M-cone contributions via outer diffuse bipolar cells and that opponent L/M-cone signals are conveyed mainly by inner S-cone bipolar cells.

Animals↗
PubMed2003

Contrast threshold of a brisk-transient ganglion cell in vitro.

We measured the contrast threshold for mammalian brisk-transient ganglion cells in vitro. Spikes were recorded extracellularly in the intact retina (guinea pig) in response to a spot with sharp onset, flashed for 100 ms over the receptive field center. Probability density functions were constructed from spike responses to stimulus contrasts that bracketed threshold. Then an "ideal observer" (IO) compared additional trials to these probability distributions and decided, using a single-interval, two-alternative forced-choice procedure, which contrasts had most likely been presented. From these decisions we constructed neurometric functions that yielded the threshold contrast by linear interpolation. Based on the number of spikes in a response, the IO detected contrasts as low as 1% [4.2 +/- 0.4% (SE); n = 35]; based on the temporal pattern of spikes, the IO detected contrasts as low as 0.8% (2.8 +/- 0.2%). Contrast increments above a very low "basal contrast" were discriminated with greater sensitivity than they were detected against the background. Performance was optimal near 37 degrees C and declined with a Q(10) of about 2, similar to that of retinal metabolism. By the method used by previous in vivo studies of brisk-transient cells, our most sensitive cells had similar thresholds. The in vitro measurements thus provide an important benchmark for comparing sensitivity of neurons upstream (cone and bipolar cell) and downstream to assess efficiency of retinal and central circuits.

Algorithms↗
PubMed2003

Two ribbon synaptic units in rod photoreceptors of macaque, human, and cat.

The rod photoreceptor's synaptic terminal (or spherule) uses an elaborate synaptic structure to signal absorption of one or more photons to its postsynaptic targets. This structure includes one or two synaptic ribbons inside the terminal and a pouch-like "invagination" outside the terminal, into which enter a widely variable number of incoming fibers and postsynaptic targets-central elements supplied by rod bipolar cells and lateral elements supplied by horizontal cells. Nonetheless, our three-dimensional reconstructions of this synaptic structure in foveal retina of macaque monkey and peripheral retina of human and cat reveal several features that are highly conserved across species and with eccentricity: 1). every spherule has one invagination; 2). with rare exceptions, every spherule has two ribbon synaptic units with these features: a). on the presynaptic side, each ribbon synaptic unit has a ribbon or part of a ribbon and one trough-shaped arciform density that demarcates its active zone; b). on the postsynaptic side, each ribbon synaptic unit has two apposed lateral elements and one or more central elements; 3). the volume of the extracellular space in the single invagination is small, approximately 0.1 microm(3); and 4). the largest distance from active zone to receptor regions on bipolar cells is small, less than approximately 1.5 microm. With such small dimensions, release of one quantum of transmitter can pulse glutamate to a concentration comparable to the EC(50) of the metabotropic glutamate receptors on the central elements associated with both synaptic units. We speculate that two ribbon synaptic units are required to sustain the high quantal release rate needed to signal a single photon.

Animals↗
PubMed2003

Matching neural morphology to molecular expression: single cell injection following immunostaining.

To match a neuron's morphology with its expression of a particular protein, it is useful to first identify the cell by immunostaining and then inject it with fluorescent dye. Such targeted injection cannot be performed with a hydrophilic dye (such as Lucifer yellow) because the neuron, once rendered porous to antibodies, does not retain it. But a lipophilic dye (such as DiI) injected iontophoretically into the soma forms a crystal and is thereby trapped. From this intracellular depot dye diffuses into the cell membrane to reveal the detailed morphology. We have used this strategy to identify the morphology of a GABAergic retinal bipolar cell and several types of GABAergic amacrine cell. In addition, we demonstrate probable connections from a narrow-field, GABAergic amacrine cell to the OFF brisk-transient ganglion cell. Finally, we show that the strategy works in the cortical slice, showing a layer IV cell immunostained for parvalbumin to be a "nest basket cell".

Amacrine Cells↗