Synaptic Transfer between Rod and Cone Pathways Mediated by AII Amacrine Cells in the Mouse Retina

Graydon, Cole W.; Lieberman, Evan E.; Rho, Nao; Briggman, Kevin L.; Singer, Joshua H.; Diamond, Jeffrey S.

doi:10.1016/j.cub.2018.06.063

Cited by 48 publications

(79 citation statements)

References 60 publications

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“…We began by skeletonizing three AII ACs distributed across serial block face electron microscopy (SBEM) volume k0725 [mouse retina; 50 × 210 × 260 µm; (Ding et al, 2016). AIIs were traced from their locations presynaptic to dyad ribbon synapses at RB terminals that were themselves identified by morphology and position within the inner plexiform layer (IPL) (Graydon et al, 2018; Mehta et al, 2014; Pallotto et al, 2015). For each of these three AIIs, we annotated all of the inputs from ribbon synapses, arising from RBs, as well as all of the conventional synaptic inputs, presumed to arise from inhibitory ACs (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…The distal (ON-layer) dendrites receive excitatory input from RBs and make electrical synapses with the axon terminals of ON cone bipolar (CB) cells, particularly type 6 CBs presynaptic to ON α GCs; depolarization of AIIs drives excitatory transmission to ON α GCs (Schwartz et al, 2012). The proximal (OFF-layer) dendrites make inhibitory glycinergic synapses onto the axon terminals of some OFF CBs [primarily type 2 CBs (Graydon et al, 2018)] and some OFF GCs, including OFF α and δ GCs as well as suppressed-by-contrast GCs (Beaudoin et al, 2019; Demb and Singer, 2012; Jacoby et al, 2015). Thus, the AII mediates so-called “cross-over” inhibition, whereby one pathway (ON, in this case) suppresses the other (OFF) and thereby decorrelates their outputs (Demb and Singer, 2015).…”

Section: Introductionmentioning

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

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Park

Lieberman

et al. 2020

Preprint

Self Cite

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“…the amacrine cell type with the highest retinal density; data not shown). To better determine the extent to which glial ensheathment is a true feature of MACs, we reconstructed Müller glia in a different block-face data set (Graydon et al, 2018) that did not have genetic labels or NIRB. Each Müller cell reconstruction (n=3) in this dataset exhibited multiple neuronal ensheathments throughout the IPL, and by reconstructing some of the ensheathed neurons (~30) we found two amacrine cells which mirrored the morphology and synaptic organization of the MAC identified using the NIRB technique ( Figure 3C).…”

Section: Macs Make Connections With Neurons and Müller Gliamentioning

confidence: 99%

“…The nature of the synaptic connections with these wide-field amacrine cells remains a mystery for future studies. Determination of bipolar cell identity was facilitated by using EM data from previously published work (Ding et al, 2016, Graydon et al, 2018. Reconstructions of the neurons providing ribbon-type input to the 2 MACs found in the non-NIRB block were successfully identified as type 5 and type 6 cone bipolar cells (see Materials and Methods).…”

Section: Which Cells Mediate Excitatory Synaptic Input To Macs? Our Ementioning

confidence: 99%

“…Right Electron micrographs of the Müller ensheathments denoted in the left panel with numbers 5 and 6. C) Müller cells reconstructed in another, nonlabelled EM block(Graydon et al, 2018) also ensheathed MACs (see Materials and Methods). left An example of a Müller cell reconstruction (red) with multiple ensheathments of an amacrine cell (blue) with morphology matching the MAC.…”

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A high-density narrow-field inhibitory retinal interneuron with direct coupling to Müller glia

Grimes¹,

Ayturk

Hoon³

et al. 2020

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Amacrine cells are interneurons comprising the most diverse cell type in the mammalian retina. They help encode visual features such as edges or directed motion by mediating excitatory and inhibitory interactions between input (i.e. bipolar) and output (i.e. ganglion) neurons in the inner plexiform layer (IPL). Like other brain regions, the retina also contains glial cells that contribute to neurotransmitter uptake, neurovascular control and metabolic regulation. Here, we report that a previously poorly characterized, but relatively abundant, inhibitory amacrine cell type in the mouse retina is coupled directly to Müller glia. Electron microscopic reconstructions of this amacrine type revealed extensive associations with Müller glia, whose processes often completely ensheathe the neurites of this amacrine cell type. Microinjections of small tracer molecules into the somas of these amacrine cells led to selective labelling of nearby Müller glia, leading us to suggest the name "Müller glia-coupled amacrine cell" or MAC. Our electrophysiological data also indicate that MACs release glycine at conventional chemical synapses with amacrine, bipolar and retinal ganglion cells (RGCs), and viral transsynaptic tracing showed connections to several known RGC types. Visually-evoked responses revealed a strong preference for light increments; these "ON" responses were primarily mediated by excitatory chemical synaptic input and direct electrical coupling to other cells. This initial characterization of the MAC provides the first evidence for neuron-glia coupling in the mammalian retina and identifies the MAC as a potential link between inhibitory processing and glial function.Significance Statement: Gap junctions between pairs of neurons or glial cells are commonly found throughout the nervous system, and play a myriad of roles including electrical coupling and metabolic exchange. In contrast, gap junctions between neurons and glia cells are rare and poorly understood. Here we report the first evidence for neuron-glia coupling in the mammalian retina, specifically between an abundant (but previously unstudied) inhibitory interneuron and Müller glia.

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The functional characteristics of optogenetic gene therapy for vision restoration

Lindner

Gilhooley

Peirson

et al. 2020

Cell. Mol. Life Sci.

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Optogenetic strategies to restore vision in patients blind from end-stage retinal degenerations aim to render remaining retinal neurons light-sensitive. We present an innovative combination of multi-electrode array recordings together with a complex pattern-generating light source as a toolset to determine the extent to which neural retinal responses to complex light stimuli can be restored following viral delivery of red-shifted channelrhodopsin in the retinally degenerated mouse. Our data indicate that retinal output level spatiotemporal response characteristics achieved by optogenetic gene therapy closely parallel those observed for normal mice but equally reveal important limitations, some of which could be mitigated using bipolarcell targeted gene-delivery approaches. As clinical trials are commencing, these data provide important new information on the capacity and limitations of channelrhodopsin-based gene therapies. The toolset we established enables comparing optogenetic constructs and stem-cell-based techniques, thereby providing an efficient and sensitive starting point to identify future approaches for vision restoration.

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Synaptic Transfer between Rod and Cone Pathways Mediated by AII Amacrine Cells in the Mouse Retina

Cited by 48 publications

References 60 publications

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

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

A high-density narrow-field inhibitory retinal interneuron with direct coupling to Müller glia

The functional characteristics of optogenetic gene therapy for vision restoration

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