A Self-Regulating Gap Junction Network of Amacrine Cells Controls Nitric Oxide Release in the Retina

Jacoby, Jason; Nath, Amurta; Jessen, Zachary F.; Schwartz, Greg

doi:10.1016/j.neuron.2018.09.047

Cited by 48 publications

(48 citation statements)

References 63 publications

(84 reference statements)

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“…Three gases have been implicated as neurotransmitters, NO, CO and H2S (Boehning and Snyder, 2003). Three AC types, C48, C52 and C54 expressed high or moderate levels of Nitric Oxide Synthase (Nos1; Figure 5I), consistent with previous reports of at least two Nos-positive AC types (Pang et al, 2010;Jacoby et al, 2018). Heme oxygenases (Hmox1, Hmox2) generate CO, with Hmox2 thought to be responsible for generating CO used as a neurotransmitter.…”

Section: Neurotransmitters and Neuromodulatorssupporting

confidence: 89%

Molecular identification of sixty-three amacrine cell types completes a mouse retinal cell atlas

Wang

et al. 2020

Preprint

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Amacrine cells (ACs) are a diverse class of interneurons that modulate input from photoreceptors to retinal ganglion cells (RGCs), rendering each RGC type selectively sensitive to particular visual features, which are then relayed to the brain. While many AC types have been identified morphologically and physiologically, they have not been comprehensively classified or molecularly characterized. We used high-throughput single-cell RNA sequencing (scRNA-seq) to profile >32,000 ACs from mouse retina, and applied computational methods to identify 63 AC types. We identified molecular markers for each type, and used them to characterize the morphology of multiple types. We show that they include nearly all previously known AC types as well as many that had not been described. Consistent with previous studies, most of the AC types express markers for the canonical inhibitory neurotransmitters GABA or glycine, but several express neither or both. In addition, many express one or more neuropeptides, and two express glutamatergic markers. We also explored transcriptomic relationships among AC types and identified transcription factors expressed by individual or multiple closely related types. Noteworthy among these were Meis2 and Tcf4, expressed by most GABAergic and most glycinergic types, respectively. Together, these results provide a foundation for developmental and functional studies of ACs, as well as means for genetically accessing them. Along with previous molecular, physiological and morphological analyses, they establish the existence of at least 130 neuronal types and nearly 140 cell types in mouse retina. SIGNIFICANCE STATEMENTThe mouse retina is a leading model for analyzing the development, structure, function and pathology of neural circuits. A complete molecular atlas of retinal cell types provides an important foundation for these studies. We used high-throughput single-cell RNA sequencing (scRNA-seq) to characterize the most heterogeneous class of retinal interneurons, amacrine cells, identifying 63 distinct types. The atlas includes types identified previously as well as many novel types. We provide evidence for use of multiple neurotransmitters and neuropeptides and identify transcription factors expressed by groups of closely related types. Combining these results with those obtained previously, we proposed that the mouse retina contains 130 neuronal types, and is therefore comparable in complexity to other regions of the brain.

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Section: Neurotransmitters and Neuromodulatorssupporting

confidence: 89%

Molecular identification of sixty-three amacrine cell types completes a mouse retinal cell atlas

Wang

et al. 2020

Preprint

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“…Cre-mediated recombination drove ChR2/eYFP reporter expression in multiple AC types in the nNOS-creER retina. We observed two AC types, called NOS-1 and NOS-2, (Jacoby et al, 2018; Zhu et al, 2014), consistent with reports of nNOS expression in at least two AC types (Chun et al, 1999; Kim et al, 1999).…”

Section: Discussionsupporting

confidence: 92%

“…We studied retinas in which Cre expression was induced robustly; these had 110 ± 5 cells mm -2 (mean ± sem) labeled in the GCL and 128 ± 5 cells mm -2 labeled in the INL (n = 7 retinas from 7 mice). Based on an earlier description of this driver line, we assumed that labeled cells in the GCL included a mixture of NOS-1 and NOS-2 ACs, with NOS-1 cells having the bistratified morphology described here and NOS-2 cells exhibiting thick, spiny dendrites that project into the central level of the IPL, between the layers marked by dendrites of ON and OFF starburst ACs (Jacoby et al, 2018; Zhu et al, 2014). Labeled cells in the INL included additional NOS-2 ACs (Zhu et al, 2014) as well as other AC types that projected into the outer most levels of the IPL but were not studied here.…”

Section: Resultsmentioning

confidence: 99%

“…NOS-2 cell membrane voltage responses to light clearly differed from those of NOS-1 cells (Figure 5D, E). NOS-2 cells were non-spiking with graded, depolarizing responses to both positive and negative contrast and are therefore ON-OFF cells (Jacoby et al, 2018). Both ON and OFF responses of NOS-2 cells increased with spot diameter, with a relatively more gradual increase for the OFF response (Figure 5F).…”

Section: Resultsmentioning

confidence: 99%

“…The NOS-1 AC is described above. The NOS-2 AC is a monostratified cell, with dendrites in the center of the IPL (between the processes of ON and OFF starburst ACs; Figure 5D); its soma is either in the conventional location in the INL (∼75%) or displaced to the GCL (∼25%) (Chun et al, 1999; Jacoby et al, 2018; Kim et al, 1999; Zhu et al, 2014). There were additional labeled ACs in the INL of the nNOS-CreER retina: their processes stratified in the OFF layers proximal to the INL, but the cells were not characterized further.…”

Section: Discussionmentioning

confidence: 99%

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Connectomic analysis reveals an interneuron with an integral role in the retinal circuit for night vision

Park

Lieberman

et al. 2020

Preprint

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18Blindness to Yale University. We thank Tim Maugel and the Laboratory for Biological 19 Ultrastructure (Department of Biology, UMD) for assistance with transmission electron 20 microscopy, Alexander Baden for assistance with 3D visualization, and Kacie Furcolo and Adit 21 Sabnis for assistance with SBEM dataset skeletonization. We thank Cole Graydon for 22 comments on the manuscript. 24 Summary 31The mammalian rod bipolar (RB) cell pathway is perhaps the best-studied circuit in the 32 vertebrate retina. Its synaptic interactions with other retinal circuits, however, remain 33 unresolved. Here, we combined anatomical and physiological analyses of the mouse retina to 34 discover that the majority of synaptic inhibition to the AII amacrine cell (AC), the central neuron 35 in the RB pathway, is provided by a single interneuron type: a multistratified, axon-bearing 36 GABAergic AC, with dendrites in both ON and OFF synaptic layers, but with a pure ON 37 (depolarizing) response to light. We used the nNOS-CreER mouse retina to confirm the identity 38 of this interneuron as the wide-field NOS-1 AC. Our study demonstrates generally that novel 39 neural circuits can be identified from targeted connectomic analyses and specifically that the 40 NOS-1 AC mediates long-range inhibition during night vision and is a major element of the RB 41 pathway. 42 43 74 remain. Most significantly, we do not know the identity of the spiking, GABAergic AC that drives 75 a receptive field surround in the AII during rod-mediated vision via synaptic inhibition of the AII 76 itself (Bloomfield and Xin, 2000); understanding mechanisms contributing to surround inhibition 77 4 is important because such inhibition tunes AII responses to spatial features of the visual 78 stimulus. 79Here, we identified the major inhibitory input to the AII by combining anatomical, genetic, 80 and electrophysiological analyses in a three-step process. One, we reconstructed ACs that 81 provided synaptic input to AIIs in a volume of mouse retina imaged by scanning block-face 82 electron microscopy [SBEM; (Denk and Horstmann, 2004)]. Two, we evaluated published 83 descriptions of reporter mouse lines to identify genetically-accessible ACs that had the 84 anatomical characteristics of the cells reconstructed from SBEM images. And three, we used 85 electrophysiological recordings and genetics-based circuit analysis to demonstrate that a 86 candidate AC, which provided the great majority of the inhibitory synaptic input to AIIs, exhibited 87 a light response predicted by its anatomy and made GABAergic synapses onto AIIs. This 88 spiking, GABAergic AC is a multistratified, ON AC denoted NOS-1 AC and identified in the 89 nNOS-CreER mouse (Zhu et al., 2014). We conclude that the NOS-1 AC is an integral 90 component of the RB pathway and a significant source of long-range inhibition during night 91 vision. More generally, our study demonstrates the utility of targeted, small-scale "connectomic" 92 analysis for identification of novel neural circuits. 94 Results 95AIIs in the ...

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Luminance adaptation

Schwartz¹,

Levine²

2021

Retinal Computation

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A Self-Regulating Gap Junction Network of Amacrine Cells Controls Nitric Oxide Release in the Retina

Cited by 48 publications

References 63 publications

Molecular identification of sixty-three amacrine cell types completes a mouse retinal cell atlas

Molecular identification of sixty-three amacrine cell types completes a mouse retinal cell atlas

Connectomic analysis reveals an interneuron with an integral role in the retinal circuit for night vision

Luminance adaptation

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