scholarly journals Thenob2mouse, a null mutation inCacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses

2006 ◽  
Vol 23 (1) ◽  
pp. 11-24 ◽  
Author(s):  
BO CHANG ◽  
JOHN R. HECKENLIVELY ◽  
PHILIPPA R. BAYLEY ◽  
NICHOLAS C. BRECHA ◽  
MURIEL T. DAVISSON ◽  
...  
Keyword(s):  
Visual Information ◽  
Synapse Formation ◽  
Dynamic Range ◽  
Outer Nuclear Layer ◽  
Glutamate Release ◽  
Plexiform Layer ◽  
Bipolar Cells ◽  
Null Mutation ◽  
Visual Responses

Glutamate release from photoreceptor terminals is controlled by voltage-dependent calcium channels (VDCCs). In humans, mutations in theCacna1fgene, encoding the α1Fsubunit of VDCCs, underlie the incomplete form of X-linked congenital stationary night blindness (CSNB2). These mutations impair synaptic transmission from rod and cone photoreceptors to bipolar cells. Here, we report anatomical and functional characterizations of the retina in thenob2(no b-wave 2) mouse, a naturally occurring mutant caused by a null mutation inCacna1f. Not surprisingly, theb-waves of both the light- and dark-adapted electroretinogram are abnormal innob2mice. The outer plexiform layer (OPL) is disorganized, with extension of ectopic neurites through the outer nuclear layer that originate from rod bipolar and horizontal cells, but not from hyperpolarizing bipolar cells. These ectopic neurites continue to express mGluR6, which is frequently associated with profiles that label with the presynaptic marker Ribeye, indicating potential points of ectopic synapse formation. However, the morphology of the presynaptic Ribeye-positive profiles is abnormal. While cone pedicles are present their morphology also appears compromised. Characterizations of visual responses in retinal ganglion cellsin vivo, under photopic conditions, demonstrate that ON-center cells have a reduced dynamic range, although their basic center-surround organization is retained; no alteration in the responses of OFF-center cells was evident. These results indicate thatnob2mice are a valuable model in which to explore the pathophysiological mechanisms associated withCacna1fmutations causing CSNB2, and the subsequent effects on visual information processing. Further, thenob2mouse represents a model system in which to define the signals that guide synapse formation and/or maintenance in the OPL.

In vivo development of retinal ON-bipolar cell axonal terminals visualized in nyx::MYFP transgenic zebrafish

2006 ◽  
Vol 23 (5) ◽  
pp. 833-843 ◽  
Author(s):  
ERIC H. SCHROETER ◽  
RACHEL O.L. WONG ◽  
RONALD G. GREGG
Keyword(s):  
Bipolar Cell ◽  
Plexiform Layer ◽  
Transgenic Fish ◽  
Bipolar Cells ◽  
Regulatory Sequences ◽  
Inner Plexiform Layer ◽  
Fixed Tissue ◽  
Different Ages ◽  
Retinal Bipolar Cells

Axonal differentiation of retinal bipolar cells has largely been studied by comparing the morphology of these interneurons in fixed tissue at different ages. To better understand how bipolar axonal terminals develop in vivo, we imaged fluorescently labeled cells in the zebrafish retina using time-lapse confocal and two photon microscopy. Using the upstream regulatory sequences from the nyx gene that encodes nyctalopin, we constructed a transgenic fish in which a subset of retinal bipolar cells express membrane targeted yellow fluorescent protein (MYFP). Axonal terminals of these YFP-labeled bipolar cells laminated primarily in the inner half of the inner plexiform layer, suggesting that they are likely to be ON-bipolar cells. Transient expression of MYFP in isolated bipolar cells indicates that two or more subsets of bipolar cells, with one or two terminal boutons, are labeled. Live imaging of YFP-expressing bipolar cells in the nyx::MYFP transgenic fish at different ages showed that initially, filopodial-like structures extend and retract from their primary axonal process throughout the inner plexiform layer (IPL). Over time, filopodial exploration becomes concentrated at discrete foci prior to the establishment of large terminal boutons, characteristic of the mature form. This sequence of axonal differentiation suggests that synaptic targeting by bipolar cell axons may involve an early process of trial and error, rather than a process of directed outgrowth and contact. Our observations represent the first in vivo visualization of axonal development of bipolar cells in a vertebrate retina.

scholarly journals Retinal Development and Pathophysiology in Kcnj13 Knockout Mice

2022 ◽  
Vol 9 ◽  
Author(s):  
Xiaodong Jiao ◽  
Zhiwei Ma ◽  
Jingqi Lei ◽  
Pinghu Liu ◽  
Xiaoyu Cai ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Knockout Mice ◽  
Ciliary Body ◽  
Outer Nuclear Layer ◽  
Plexiform Layer ◽  
Bipolar Cells ◽  
Conditional Knockout ◽  
Intron 1 ◽  
Vitreoretinal Degeneration ◽  
Inwardly Rectifying

Purpose: We constructed and characterized knockout and conditional knockout mice for KCNJ13, encoding the inwardly rectifying K+ channel of the Kir superfamily Kir7.1, mutations in which cause both Snowflake Vitreoretinal Degeneration (SVD) and Retinitis pigmentosa (RP) to further elucidate the pathology of this disease and to develop a potential model system for gene therapy trials.Methods: A Kcnj13 knockout mouse line was constructed by inserting a gene trap cassette expressing beta-galactosidase flanked by FRT sites in intron 1 with LoxP sites flanking exon two and converted to a conditional knockout by FLP recombination followed by crossing with C57BL/6J mice having Cre driven by the VMD2 promoter. Lentiviral replacement of Kcnj13 was driven by the EF1a or VMD2 promoters.Results: Blue-Gal expression is evident in E12.5 brain ventricular choroid plexus, lens, neural retina layer, and anterior RPE. In the adult eye expression is seen in the ciliary body, RPE and choroid. Adult conditional Kcnj13 ko mice show loss of photoreceptors in the outer nuclear layer, inner nuclear layer thinning with loss of bipolar cells, and thinning and disruption of the outer plexiform layer, correlating with Cre expression in the overlying RPE which, although preserved, shows morphological disruption. Fundoscopy and OCT show signs of retinal degeneration consistent with the histology, and photopic and scotopic ERGs are decreased in amplitude or extinguished. Lentiviral based replacement of Kcnj13 resulted in increased ERG c- but not a- or b- wave amplitudes.Conclusion: Ocular KCNJ13 expression starts in the choroid, lens, ciliary body, and anterior retina, while later expression centers on the RPE with no/lower expression in the neuroretina. Although KCNJ13 expression is not required for survival of the RPE, it is necessary for RPE maintenance of the photoreceptors, and loss of the photoreceptor, outer plexiform, and outer nuclear layers occur in adult KCNJ13 cKO mice, concomitant with decreased amplitude and eventual extinguishing of the ERG and signs of retinitis pigmentosa on fundoscopy and OCT. Kcnj13 replacement resulting in recovery of the ERG c- but not a- and b-waves is consistent with the degree of photoreceptor degeneration seen on histology.

scholarly journals Neuromodulation of excitatory synaptogenesis in striatal development

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Yevgenia Kozorovitskiy ◽  
Rui Peixoto ◽  
Wengang Wang ◽  
Arpiar Saunders ◽  
Bernardo L Sabatini
Keyword(s):  
Developmental Plasticity ◽  
Synapse Formation ◽  
Glutamate Release ◽  
Projection Neurons ◽  
Excitatory Synapses ◽  
Indirect Pathway ◽  
Protein Receptors ◽  
In Vivo Effects

Dopamine is released in the striatum during development and impacts the activity of Protein Kinase A (PKA) in striatal spiny projection neurons (SPNs). We examined whether dopaminergic neuromodulation regulates activity-dependent glutamatergic synapse formation in the developing striatum. Systemic in vivo treatment with Gαs-coupled G-protein receptors (GPCRs) agonists enhanced excitatory synapses on direct pathway striatal spiny projection neurons (dSPNs), whereas rapid production of excitatory synapses on indirect pathway neurons (iSPNs) required the activation of Gαs GPCRs in SPNs of both pathways. Nevertheless, in vitro Gαs activation was sufficient to enhance spinogenesis induced by glutamate photolysis in both dSPNs and iSPNs, suggesting that iSPNs in intact neural circuits have additional requirements for rapid synaptic development. We evaluated the in vivo effects of enhanced glutamate release from corticostriatal axons and postsynaptic PKA and discovered a mechanism of developmental plasticity wherein rapid synaptogenesis is promoted by the coordinated actions of glutamate and postsynaptic Gαs-coupled receptors.

scholarly journals The effects of early diabetes on inner retinal neurons

2020 ◽  
Vol 37 ◽  
Author(s):  
Erika D. Eggers ◽  
Teresia A. Carreon
Keyword(s):  
Ganglion Cells ◽  
Early Stage ◽  
Glutamate Release ◽  
Amacrine Cells ◽  
Gaba Release ◽  
Bipolar Cells ◽  
Gamma Aminobutyric Acid ◽  
Early Diabetes

Abstract Diabetic retinopathy is now well understood as a neurovascular disease. Significant deficits early in diabetes are found in the inner retina that consists of bipolar cells that receive inputs from rod and cone photoreceptors, ganglion cells that receive inputs from bipolar cells, and amacrine cells that modulate these connections. These functional deficits can be measured in vivo in diabetic humans and animal models using the electroretinogram (ERG) and behavioral visual testing. Early effects of diabetes on both the human and animal model ERGs are changes to the oscillatory potentials that suggest dysfunctional communication between amacrine cells and bipolar cells as well as ERG measures that suggest ganglion cell dysfunction. These are coupled with changes in contrast sensitivity that suggest inner retinal changes. Mechanistic in vitro neuronal studies have suggested that these inner retinal changes are due to decreased inhibition in the retina, potentially due to decreased gamma aminobutyric acid (GABA) release, increased glutamate release, and increased excitation of retinal ganglion cells. Inner retinal deficits in dopamine levels have also been observed that can be reversed to limit inner retinal damage. Inner retinal targets present a promising new avenue for therapies for early-stage diabetic eye disease.

scholarly journals Pharmacology of the skate electroretinogram indicates independent ON and OFF bipolar cell pathways.

1996 ◽  
Vol 107 (4) ◽  
pp. 535-544 ◽  
Author(s):  
R L Chappell ◽  
F J Rosenstein
Keyword(s):  
Bipolar Cell ◽  
Visual Information ◽  
Plexiform Layer ◽  
Bipolar Cells ◽  
Inner Plexiform Layer ◽  
Critical Feature ◽  
Single Class ◽  
Afferent Pathways ◽  
Afferent Information ◽  
On And Off Pathways

Organization of afferent information into parallel ON and OFF pathways is a critical feature of the vertebrate visual system. All afferent visual information in the vertebrate retina reaches the inner plexiform layer (IPL) via bipolar cells. It is at the bipolar cell level that separation of ON and OFF information first appears for afferent information from cones. This may also hold true for the rod pathway of cold-blooded vertebrates, but not for mammals. The all-rod retina of the skate presents an opportunity to examine such pathways in a retina having but a single class of photoreceptor. Immunocytochemical evidence suggests that both ON and OFF bipolar cells are present in the skate retina. We examined the pharmacology of the skate electroretinogram (ERG) to test the hypothesis that independent ON and OFF bipolar cell pathways are functional as rod afferent pathways from outer to inner plexiform layer in the skate. 100 microM 2-amino-4-phosphonobutyric acid (APB) reversibly blocked the skate ERG b-wave. A small d-wave-like OFF component of the ERG revealed by DC recording of response to a prolonged (10 s) flash of light was reduced or blocked by 5 mM kynurenic acid (KYN). We found that addition of 200 microM picrotoxin to the Ringer's solution revealed prominent ON and OFF components of the skate ERG while reducing the c-wave. These ON and OFF components were reversibly blocked by 100 microM APB and 5 mM KYN, respectively. Reversible block of the OFF component by KYN was also accomplished in the presence of 500 microM N-methyl-DL-aspartate. From these findings, we conclude that ON and OFF bipolar cells are likely to be functional as parallel afferent interplexiform pathways in the all-rod retina of the skate.

scholarly journals In vivo Morphometry of Inner Plexiform Layer (IPL) Stratification in the Human Retina With Visible Light Optical Coherence Tomography

2021 ◽  
Vol 15 ◽  
Author(s):  
Tingwei Zhang ◽  
Aaron M. Kho ◽  
Vivek J. Srinivasan
Keyword(s):  
Optical Coherence Tomography ◽  
Visual System ◽  
Visible Light ◽  
Human Subjects ◽  
Plexiform Layer ◽  
Bipolar Cells ◽  
Inner Plexiform Layer ◽  
Optical Coherence ◽  
On And Off Pathways

From the bipolar cells to higher brain visual centers, signals in the vertebrate visual system are transmitted along parallel on and off pathways. These two pathways are spatially segregated along the depth axis of the retina. Yet, to our knowledge, there is no way to directly assess this anatomical stratification in vivo. Here, employing ultrahigh resolution visible light Optical Coherence Tomography (OCT) imaging in humans, we report a stereotyped reflectivity pattern of the inner plexiform layer (IPL) that parallels IPL stratification. We characterize the topography of this reflectivity pattern non-invasively in a cohort of normal, young adult human subjects. This proposed correlate of IPL stratification is accessible through non-invasive ocular imaging in living humans. Topographic variations should be carefully considered when designing studies in development or diseases of the visual system.

Temporal Modulation of Scotopic Visual Signals by A17 Amacrine Cells in Mammalian Retina In Vivo

2003 ◽  
Vol 89 (4) ◽  
pp. 2159-2166 ◽  
Author(s):  
Cun-Jian Dong ◽  
William A. Hare
Keyword(s):  
Light Intensity ◽  
Visual Information ◽  
Amacrine Cells ◽  
Bipolar Cells ◽  
Visual Signals ◽  
Temporal Properties ◽  
Mammalian Retina ◽  
Show Evidence ◽  
Light Stimuli

We examined function of the feedback pathway from A17 GABAergic amacrine cells to rod bipolar cells (A17 feedback), a critically located inhibitory circuit in the classic rod pathway of the mammalian retina whose role in processing of scotopic visual information is still poorly understood. We show evidence that this A17 feedback has a profound influence on the temporal properties of rod-driven postphotoreceptoral responses (assessed with the scotopic electroretinogram b-wave). Application of a GABAcantagonist prolonged preferentially the decay of the scotopic b-wave. The degree of prolongation increased as the light intensity decreased. Application of selective GABAa antagonists accelerated the kinetics of the scotopic b-wave. This effect was abolished when the GABAc antagonist was coapplied. Selective ablation of A17 cells mimicked the action of the GABAc antagonist. In A17 cell–ablated retinas, the GABAc antagonist was no longer very effective to slow the decay of the scotopic b-wave. Thus the A17 feedback, activated by light stimulation and mediated mainly by the GABAc receptors, makes the scotopic b-wave more transient by accelerating preferentially its decay. The strength of the feedback can be modulated by GABAa receptor–mediated inhibition and by light intensity. Our results also suggest that in the mammalian retina the feedback may be a novel mechanism that contributes postphotoreceptorally to the termination of rod signals, especially those elicited by very dim light stimuli.

scholarly journals Synaptic Remodeling in the Cone Pathway After Early Postnatal Horizontal Cell Ablation

2021 ◽  
Vol 15 ◽  
Author(s):  
Lena Nemitz ◽  
Karin Dedek ◽  
Ulrike Janssen-Bienhold
Keyword(s):  
Synapse Formation ◽  
Outer Nuclear Layer ◽  
Horizontal Cell ◽  
Bipolar Cells ◽  
Horizontal Cells ◽  
Mouse Retina ◽  
Retina Development ◽  
Synaptic Remodeling ◽  
Cell Ablation ◽  
Cone Pathway

The first synapse of the visual pathway is formed by photoreceptors, horizontal cells and bipolar cells. While ON bipolar cells invaginate into the photoreceptor terminal and form synaptic triads together with invaginating horizontal cell processes, OFF bipolar cells make flat contacts at the base of the terminal. When horizontal cells are ablated during retina development, no invaginating synapses are formed in rod photoreceptors. However, how cone photoreceptors and their synaptic connections with bipolar cells react to this insult, is unclear so far. To answer this question, we specifically ablated horizontal cells from the developing mouse retina. Following ablation around postnatal day 4 (P4)/P5, cones initially exhibited a normal morphology and formed flat contacts with OFF bipolar cells, but only few invaginating contacts with ON bipolar cells. From P15 on, synaptic remodeling became obvious with clustering of cone terminals and mislocalized cone somata in the OPL. Adult cones (P56) finally displayed highly branched axons with numerous terminals which contained ribbons and vesicular glutamate transporters. Furthermore, type 3a, 3b, and 4 OFF bipolar cell dendrites sprouted into the outer nuclear layer and even expressed glutamate receptors at the base of newly formed cone terminals. These results indicate that cones may be able to form new synapses with OFF bipolar cells in adult mice. In contrast, cone terminals lost their invaginating contacts with ON bipolar cells, highlighting the importance of horizontal cells for synapse maintenance. Taken together, our data demonstrate that early postnatal horizontal cell ablation leads to differential remodeling in the cone pathway: whereas synapses between cones and ON bipolar cells were lost, new putative synapses were established between cones and OFF bipolar cells. These results suggest that synapse formation and maintenance are regulated very differently between flat and invaginating contacts at cone terminals.

scholarly journals Synaptic release at mammalian bipolar cell terminals

2011 ◽  
Vol 28 (1) ◽  
pp. 109-119 ◽  
Author(s):  
QUN-FANG WAN ◽  
RUTH HEIDELBERGER
Keyword(s):  
Bipolar Cell ◽  
Neurotransmitter Release ◽  
Visual Information ◽  
Glutamate Release ◽  
Vital Role ◽  
Bipolar Cells ◽  
Intrinsic Factors ◽  
Synaptic Release ◽  
Presynaptic Mechanisms ◽  
Rod Bipolar Cells

AbstractBipolar cells play a vital role in the transfer of visual information across the vertebrate retina. The synaptic output of these neurons is regulated by factors that are extrinsic and intrinsic. Relatively little is known about the intrinsic factors that regulate neurotransmitter exocytosis. Much of what we know about intrinsic presynaptic mechanisms that regulate glutamate release has come from the study of the unusually large and accessible synaptic terminal of the goldfish rod-dominant bipolar cell, the Mb1 bipolar cell. However, over the past several years, examination of presynaptic mechanisms governing neurotransmitter release has been extended to the mammalian rod bipolar cell. In this review, we discuss the recent advances in our understanding of synaptic vesicle dynamics and neurotransmitter release in rodent rod bipolar cells and consider how these properties help to shape the synaptic output of the mammalian retina.

scholarly journals An amplitude code increases the efficiency of information transmission across a visual synapse

2018 ◽  
Author(s):  
Ben James ◽  
Léa Darnet ◽  
José Moya-Díaz ◽  
Sofie-Helene Seibel ◽  
Leon Lagnado
Keyword(s):  
Synaptic Vesicles ◽  
Visual Information ◽  
Dynamic Range ◽  
Bipolar Cells ◽  
Visual Signals ◽  
Temporal Precision ◽  
Ribbon Synapses ◽  
Analogue Signals ◽  
Rate Coding ◽  
The Brain

Most neurons in the brain transmit information digitally using sequences of spikes that trigger release of synaptic vesicles of fixed size. The first stages of vision and hearing are distinct in operating with analogue signals, but it is unclear how these are recoded for synaptic transmission. By imaging the release of glutamate in live zebrafish, we demonstrate how ribbon synapses of retinal bipolar cells transmit analogue visual signals by changes in both the rate and amplitude of synaptic events. Higher contrasts released glutamate packets composed of more vesicles and coding by amplitude often continued after rate coding had saturated. Glutamate packets equivalent to five vesicles transmitted four times as many bits of information per vesicle compared to independent release events. By discretizing analogue signals into sequences of numbers ranging up to eleven, ribbon synapses increase the dynamic range, temporal precision and efficiency with which visual information is transmitted.

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