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1.  Visual space is represented by non-matching topographies of distinct mouse retinal ganglion cell types 
Current biology : CB  2014;24(3):310-315.
Summary
The distributions of neurons in sensory circuits display ordered spatial patterns arranged to enhance or encode specific regions or features of the external environment. Indeed, visual space is not sampled uniformly across the vertebrate retina. Retinal ganglion cell (RGC) density increases and dendritic arbor size decreases towards retinal locations with higher sampling frequency, such as the fovea in primates and area centralis in carnivores [1]. In these locations, higher acuity at the level of individual cells is obtained because the receptive field center of a RGC corresponds approximately to the spatial extent of its dendritic arbor [2, 3]. For most species, structurally and functionally distinct RGC types appear to have similar topographies; collectively scaling their cell densities and arbor sizes towards the same retina location [4]. Thus, visual space is represented across the retina in parallel by multiple distinct circuits [5]. In contrast, we find a population of mouse RGCs, known as alpha or alpha-like [6], that displays a nasal-to-temporal gradient in cell density, size and receptive fields, which facilitates enhanced visual sampling in frontal visual fields. The distribution of alpha-like RGCs contrasts with other known mouse RGC types, and suggests that unlike most mammals, RGC topographies in mice are arranged to sample space differentially.
doi:10.1016/j.cub.2013.12.020
PMCID: PMC3990865  PMID: 24440397
2.  Differential Progression of Structural and Functional Alterations in Distinct Retinal Ganglion Cell Types in a Mouse Model of Glaucoma 
The Journal of Neuroscience  2013;33(44):17444-17457.
Intraocular pressure (IOP) elevation is a principal risk factor for glaucoma. Using a microbead injection technique to chronically raise IOP for 15 or 30 d in mice, we identified the early changes in visual response properties of different types of retinal ganglion cells (RGCs) and correlated these changes with neuronal morphology before cell death. Microbead-injected eyes showed reduced optokinetic tracking as well as cell death. In such eyes, multielectrode array recordings revealed that four RGC types show diverse alterations in their light responses upon IOP elevation. OFF-transient RGCs exhibited a more rapid decline in both structural and functional organizations compared with other RGCs. In contrast, although the light-evoked responses of OFF-sustained RGCs were perturbed, the dendritic arbor of this cell type remained intact. ON-transient and ON-sustained RGCs had normal functional receptive field sizes but their spontaneous and light-evoked firing rates were reduced. ON- and OFF-sustained RGCs lost excitatory synapses across an otherwise structurally normal dendritic arbor. Together, our observations indicate that there are changes in spontaneous activity and light-evoked responses in RGCs before detectable dendritic loss. However, when dendrites retract, we found corresponding changes in receptive field center size. Importantly, the effects of IOP elevation are not uniformly manifested in the structure and function of diverse RGC populations, nor are distinct RGC types perturbed within the same time-frame by such a challenge.
doi:10.1523/JNEUROSCI.5461-12.2013
PMCID: PMC3812509  PMID: 24174678
3.  Developmental regulation and activity-dependent maintenance of GABAergic presynaptic inhibition onto rod bipolar cell axonal terminals 
Neuron  2013;78(1):124-137.
SUMMARY
Presynaptic inhibition onto axons regulates neuronal output, but how such inhibitory synapses develop and are maintained in vivo remains unclear. Axon terminals of glutamatergic retinal rod bipolar cells (RBCs) receive GABAA and GABAC receptor-mediated synaptic inhibition. We found that perturbing GABAergic or glutamatergic neurotransmission does not prevent GABAergic synaptogenesis onto RBC axons. But, GABA release is necessary for maintaining axonal GABA receptors. This activity-dependent process is receptor subtype specific: GABAC receptors are maintained, whereas GABAA receptors containing α1, but not α3 subunits, decrease over time in mice with deficient GABA synthesis. GABAA receptor distribution on RBC axons is unaffected in GABAC receptor knockout mice. Thus, GABAA and GABAC receptor maintenance are regulated separately. Although immature RBCs elevate their glutamate release when GABA synthesis is impaired, homeostatic mechanisms ensure that the RBC output operates within its normal range after eye-opening, perhaps to regain proper visual processing within the scotopic pathway.
doi:10.1016/j.neuron.2013.01.037
PMCID: PMC3627184  PMID: 23583111
4.  Diverse strategies engaged in establishing stereotypic wiring patterns among neurons sharing a common input at the visual system's first synapse 
Sensory circuits use common strategies such as convergence and divergence, typically at different synapses, to pool or distribute inputs. Inputs from different presynaptic cell types converge onto a common postsynaptic cell, acting together to shape neuronal output (Klausberger and Somogyi, 2008). Also, individual presynaptic cells contact several postsynaptic cell types, generating divergence of signals. Attaining such complex wiring patterns relies on the orchestration of many events across development, including axonal and dendritic growth and synapse formation and elimination (reviewed by Waites et al., 2005; Sanes and Yamagata, 2009). Recent work has focused on how distinct presynaptic cell types form stereotypic connections with an individual postsynaptic cell (Williams et al., 2011; Morgan et al., 2011), but how a single presynaptic cell type diverges to form distinct wiring patterns with multiple postsynaptic cell types during development remains unexplored. Here we take advantage of the compactness of the visual system's first synapse to observe development of such a circuit in mouse retina. By imaging three types of postsynaptic bipolar cells and their common photoreceptor targets across development, we found that distinct bipolar cell types engage in disparate dendritic growth behaviors, exhibit targeted or exploratory approaches to contact photoreceptors, and adhere differently to the synaptotropic model of establishing synaptic territories. Furthermore each type establishes their final connectivity patterns with the same afferents on separate time-scales. We propose that such differences in strategy and timeline could facilitate the division of common inputs among multiple postsynaptic cell types to create parallel circuits with diverse function.
doi:10.1523/JNEUROSCI.1581-12.2012
PMCID: PMC3435432  PMID: 22836264
5.  Sensory experience shapes the development of the visual system’s first synapse 
Neuron  2013;80(5):1159-1166.
Summary
Specific connectivity patterns among neurons create the basic architecture underlying parallel processing in our nervous system. Here we focus on the visual system’s first synapse to examine the structural and functional consequences of sensory deprivation on the establishment of parallel circuits. Dark rearing reduces synaptic strength between cones and cone bipolar cells, a previously unappreciated effect of sensory deprivation. In contrast, rod bipolar cells, which utilize the same glutamate receptor to contact rods, are unaffected by dark rearing. Underlying the physiological changes, we find the localization of metabotropic glutamate receptors within cone bipolar, but not rod bipolar, cell dendrites is a light-dependent process. Furthermore, although cone bipolar cells share common cone partners, each bipolar cell type we examined depends differentially on sensory input to achieve mature connectivity. Thus, visual experience differentially affects maturation of rod versus cone pathways and of cell types within the cone pathway.
doi:10.1016/j.neuron.2013.09.024
PMCID: PMC3894852  PMID: 24314727
6.  Identifying roles for neurotransmission in circuit assembly: Insights gained from multiple model systems and experimental approaches 
In the adult nervous system, chemical neurotransmission between neurons is essential for information processing. However, neurotransmission is also important for patterning circuits during development, but its precise roles have yet to be identified, and some remain highly debated. Here, we highlight viewpoints that have come to be widely accepted or still challenged. We discuss how distinct techniques and model systems employed to probe the developmental role of neurotransmission may reconcile disparate ideas. We underscore how the effects of perturbing neurotransmission during development vary with model systems, the stage of development when transmission is altered, the nature of the perturbation, and how connectivity is assessed. Based on findings in circuits with connectivity arranged in layers, we raise the possibility that there exist constraints in neuronal network design that limit the role of neurotransmission. We propose that activity-dependent mechanisms are effective in refining connectivity patterns only when inputs from different cells are close enough spatially to influence each other’s outcome.
doi:10.1002/bies.201000095
PMCID: PMC4019509  PMID: 21110347
neuronal connectivity; synaptic transmission; circuit refinement; synapse formation; synapse elimination
7.  Spatial Relationships between GABAergic and Glutamatergic Synapses on the Dendrites of Distinct Types of Mouse Retinal Ganglion Cells across Development 
PLoS ONE  2013;8(7):e69612.
Neuronal output requires a concerted balance between excitatory and inhibitory (I/E) input. Like other circuits, inhibitory synaptogenesis in the retina precedes excitatory synaptogenesis. How then do neurons attain their mature balance of I/E ratios despite temporal offset in synaptogenesis? To directly compare the development of glutamatergic and GABAergic synapses onto the same cell, we biolistically transfected retinal ganglion cells (RGCs) with PSD95CFP, a marker of glutamatergic postsynaptic sites, in transgenic Thy1­YFPγ2 mice in which GABAA receptors are fluorescently tagged. We mapped YFPγ2 and PSD95CFP puncta distributions on three RGC types at postnatal day P12, shortly before eye opening, and at P21 when robust light responses in RGCs are present. The mature IGABA/E ratios varied among ON-Sustained (S) A-type, OFF-S A-type, and bistratified direction selective (DS) RGCs. These ratios were attained at different rates, before eye-opening for ON-S and OFF-S A-type, and after eye-opening for DS RGCs. At both ages examined, the IGABA/E ratio was uniform across the arbors of the three RGC types. Furthermore, measurements of the distances between neighboring PSD95CFP and YFPγ2 puncta on RGC dendrites indicate that their local relationship is established early in development, and cannot be predicted by random organization. These close spatial associations between glutamatergic and GABAergic postsynaptic sites appear to represent local synaptic arrangements revealed by correlative light and EM reconstructions of a single RGC's dendrites. Thus, although RGC types have different IGABA/E ratios and establish these ratios at separate rates, the local relationship between excitatory and inhibitory inputs appear similarly constrained across the RGC types studied.
doi:10.1371/journal.pone.0069612
PMCID: PMC3724919  PMID: 23922756
8.  Development of Cell Type-Specific Connectivity Patterns of Converging Excitatory Axons in the Retina 
Neuron  2011;71(6):1014-1021.
Summary
To integrate information from different presynaptic cell types, dendrites receive distinct patterns of synapses from converging axons. How different afferents in vivo establish specific connectivity patterns with the same dendrite is poorly understood. Here, we examine the synaptic development of three glutamatergic bipolar cell types converging onto a common postsynaptic retinal ganglion cell. We find that after axons and dendrites target appropriate synaptic layers, patterns of connections among these neurons diverge through selective changes in the conversion of axo-dendritic appositions to synapses. This process is differentially regulated by neurotransmission, which is required for the shift from single to multisynaptic appositions of one bipolar cell type but not for maintenance and elimination, respectively, of connections from the other two types. Thus, synaptic specificity among converging excitatory inputs in the retina emerges via differential synaptic maturation of axo-dendritic appositions and is shaped by neurotransmission in a cell type-dependent manner.
doi:10.1016/j.neuron.2011.08.025
PMCID: PMC3184549  PMID: 21943599
9.  Topography and Morphology of the Inhibitory Projection From Superior Olivary Nucleus to Nucleus Laminaris in Chickens (Gallus gallus) 
The avian nucleus laminaris (NL) is involved in computation of interaural time differences (ITDs) that encode the azimuthal position of a sound source. Neurons in NL are bipolar, with dorsal and ventral dendritic arbors receiving input from separate ears. NL neurons act as coincidence detectors that respond maximally when input from each ear arrives at the two dendritic arbors simultaneously. Computational and physiological studies demonstrated that the sensitivity of NL neurons to coincident inputs is modulated by an inhibitory feedback circuit via the superior olivary nucleus (SON). To understand the mechanism of this modulation, the topography of the projection from SON to NL was mapped, and the morphology of the axon terminals of SON neurons in NL was examined in chickens (Gallus gallus). In vivo injection of AlexaFluor 568 dextran amine into SON demonstrated a coarse topographic projection from SON to NL. Retrogradely labeled neurons in NL were located within the zone of anterogradely labeled terminals, suggesting a reciprocal projection from SON to NL. In vivo extracellular physiological recording further demonstrated that this topography is consistent with tonotopic maps in SON and NL. In addition, three-dimensional reconstruction of single SON axon branches within NL revealed that individual SON neurons innervate a large area of NL and terminate on both dorsal and ventral dendritic arbors of NL neurons. The organization of the projection from SON to NL supports its proposed functions of controlling the overall activity level of NL and enhancing the specificity of frequency mapping and ITD detection.
doi:10.1002/cne.22523
PMCID: PMC3299086  PMID: 21165979
auditory brainstem; axonal projection; γ-aminobutyric acid (GABA); interaural time difference (ITD); tonotopic organization
10.  In vivo development of outer retinal synapses in the absence of glial contact 
Astroglia secrete factors that promote synapse formation and maintenance. In culture, glial contact has also been shown to facilitate synaptogenesis. Here, we examined whether glial contact is important for establishing circuits in vivo by simultaneously monitoring differentiation of glial cells and local synaptogenesis over time. Photoreceptor circuits of the vertebrate retina are particularly suitable for this study because of the relatively simple, laminar organization of their connectivity with their target neurons, horizontal cells (HCs) and bipolar cells. Also, individual photoreceptor terminals are ensheathed within the outer plexiform layer (OPL) by the processes of one type of glia, Müller glia (MG). We conducted in vivo time-lapse multiphoton imaging of the rapidly-developing and relatively transparent zebrafish retina to ascertain the time course of MG development relative to OPL synaptogenesis. The emergence of synaptic triads, indicative of functional photoreceptor circuits, and structural association with glial processes were also examined across ages by electron microscopy. We first show that MG processes form territories that tile within the inner and outer synaptic layers. We then demonstrate that cone photoreceptor synapses are assembled before the elaboration of MG processes in the OPL. Using a targeted cell ablation approach, we also determined whether the maintenance of photoreceptor synapses is perturbed when local MG are absent. We found that removal of MG had no appreciable effect on the stability of newly formed cone synapses. Thus, in contrast to other CNS circuits, contact from glia is not necessary for the formation or immediate stabilization of outer retinal synapses.
doi:10.1523/JNEUROSCI.3391-10.2010
PMCID: PMC2946228  PMID: 20826659
retina; glia; photoreceptor; live-cell imaging; horizontal cell; synaptogenesis
11.  Wild type cone photoreceptors persist despite neighboring mutant cone degeneration 
In many retinal diseases, the malfunction that results in photoreceptor loss occurs only in either rods or cones, but degeneration can progress from the affected cell type to its healthy neighbors. Specifically, in human and mouse models of Retinitis Pigmentosa the loss of rods results in the death of neighboring healthy cones. Significantly less is known about cone-initiated degenerations and their affect on neighboring cells. Sometimes rods remain normal after cone death, whereas other patients experience a loss of scotopic vision over time. The affect of cone death on neighboring cones is unknown. The zebrafish is a cone-rich animal model in which the potential for dying cones to kill neighboring healthy cones can be evaluated. We previously reported that the zebrafish cone phosphodiesterase mutant (pde6cw59) displays a rapid death of cones soon after their formation and a subsequent loss of rods in the central retina. In this study we examine morphological changes associated with cone death in vivo in pde6cw59 fish. We then use blastulae transplantations to create chimeric fish with a photoreceptor layer of mixed wild type (WT) and pde6cw59 cones. We find that the death of inoperative cones does not cause neighboring WT cone loss. The survival of WT cones is independent of transplant size and location within the retina. Furthermore, transplanted WT cones persist at least several weeks after the initial death of dysfunctional mutant cones. Our results suggest a potential for the therapeutic transplantation of healthy cones into an environment of damaged cones.
doi:10.1523/JNEUROSCI.5019-09.2010
PMCID: PMC2805452  PMID: 20053919
Photoreceptors; Bystander Effect; Zebrafish; Apoptosis; Phosphodiesterase; Retinal Degeneration
12.  Cone Survival Despite Rod Degeneration in XOPS-mCFP Transgenic Zebrafish 
PURPOSE
In animal models of retinitis pigmentosa, rod photoreceptor degeneration eventually leads to loss of cone photoreceptors. The purpose of this study was to characterize a transgenic model of rod degeneration in zebrafish.
METHODS
Zebrafish transgenic for XOPS-mCFP, a membrane-targeted form of cyan fluorescent protein driven by the Xenopus rhodopsin promoter, were generated by plasmid injection. Immunohistochemistry was used to detect cell type, proliferation, and TUNEL markers in larval and adult retinas. Rod- and cone-specific transcripts were detected by RT-PCR. Visual responses in transgenic adults were measured by electroretinogram.
RESULTS
The XOPS promoter directed specific expression of mCFP in rods by 55 hours post fertilization (hpf). Rods in XOPS-mCFP heterozygotes began dying at 3.5 days post fertilization (dpf) and were almost completely absent by 5 dpf. A few rods were observed at the retinal margin, and numerous immature rods were observed in the outer nuclear layer (ONL) of transgenic adults. Apoptosis was increased in the ONL of larval and adult transgenic animals, and an elevation of rod precursor proliferation in adults was observed. ERG analysis confirmed that rod responses were absent in this line. Cone morphology and electrophysiology appeared normal in transgenic animals up to 7 months of age.
CONCLUSIONS
The XOPS-mCFP transgene causes selective degeneration of rods without secondary loss of cones in animals up to 7 months of age. This raises important questions about the significance of rod-cone interactions in zebrafish and their potential as a model of human inherited retinal degenerations.
doi:10.1167/iovs.05-0797
PMCID: PMC2810103  PMID: 16303977
13.  Transient neurites of retinal horizontal cells exhibit columnar tiling via homotypic interactions 
Nature neuroscience  2008;12(1):35-43.
Sensory neurons with common function are often non-randomly arranged and form dendritic territories that exhibit little overlap or tiling. Repulsive homotypic interactions underlie such patterns in cell organization in invertebrate neurons. In mammalian retinal horizontal cells, however, it is unclear how dendro-dendritic repulsive interactions can produce a non-random distribution of cells and their spatial territories because mature horizontal cell dendrites overlap substantially. By imaging developing mouse horizontal cells, we found that upon reaching their final laminar positions, these cells transiently elaborate vertical neurites that form non-overlapping columnar territories. Targeted cell ablation revealed that the vertical neurites engage in homotypic interactions resulting in tiling of neighboring cells prior to establishment of their dendritic fields. This developmental tiling of transient neurites correlates with the emergence of a non-random distribution of the cells, and could represent a mechanism that organizes neighbor relationships and territories of neurons of the same type before circuit assembly.
doi:10.1038/nn.2236
PMCID: PMC2743396  PMID: 19060895
14.  A precisely timed asynchronous pattern of ON and OFF retinal ganglion cell activity during propagation of retinal waves 
Neuron  2008;58(6):851-858.
Summary
Patterns of coordinated spontaneous activity have been proposed to guide circuit refinement in many parts of the developing nervous system. It is unclear, however, how such patterns, which are thought to indiscriminately synchronize nearby cells, could provide the cues necessary to segregate functionally distinct circuits within overlapping cell populations. Here we report that glutamatergic retinal waves possess a novel substructure in the bursting of neighboring retinal ganglion cells with opposite light responses (ON or OFF). Within a wave, cells fire repetitive non-overlapping bursts in a fixed order: ON before OFF. This pattern is absent from cholinergic waves, which precede glutamate-dependent activity, providing a developmental sequence of distinct activity-encoded cues. Asynchronous bursting of ON and OFF retinal ganglion cells depends on inhibition between these parallel pathways. Similar asynchronous activity patterns could arise throughout the nervous system as inhibition matures and might help to separate connections of functionally distinct subnetworks.
doi:10.1016/j.neuron.2008.04.025
PMCID: PMC2553397  PMID: 18579076
15.  In vivo imaging reveals dendritic targeting of laminated afferents by zebrafish retinal ganglion cells 
Neuron  2006;52(4):609-621.
SUMMARY
Targeting of axons and dendrites to particular synaptic laminae is an important mechanism by which precise patterns of neuronal connectivity are established. Although axons target specific laminae during development, dendritic lamination has been thought to occur largely by pruning of inappropriately placed arbors. We discovered by in vivo time-lapse imaging, that retinal ganglion cell (RGC) dendrites in zebrafish show growth patterns implicating dendritic targeting as a mechanism for contacting appropriate synaptic partners. Populations of RGCs labeled in transgenic animals establish distinct dendritic strata sequentially, predominantly from the inner to outer retina. Imaging individual cells over successive days confirmed that multistratified RGCs generate strata sequentially, each arbor elaborating within a specific lamina. Simultaneous imaging of RGCs and subpopulations of presynaptic amacrine interneurons revealed that RGC dendrites appear to target amacrine plexuses that had already laminated. Dendritic targeting of pre-patterned afferents may thus be a novel mechanism for establishing proper synaptic connectivity.
doi:10.1016/j.neuron.2006.10.004
PMCID: PMC1716713  PMID: 17114046

Results 1-15 (15)