Retinal remodeling

Abstract

Retinal photoreceptor degeneration takes many forms. Mutations in rhodopsin genes or disorders of the retinal pigment epithelium, defects in the adenosine triphosphate binding cassette transporter, ABCR gene defects, receptor tyrosine kinase defects, ciliopathies and transport defects, defects in both transducin and arrestin, defects in rod cyclic guanosine 3',5'-monophosphate phosphodiesterase, peripherin defects, defects in metabotropic glutamate receptors, synthetic enzymatic defects, defects in genes associated with signaling, and many more can all result in retinal degenerative disease like retinitis pigmentosa (RP) or RP-like disorders. Age-related macular degeneration (AMD) and AMD-like disorders are possibly due to a constellation of potential gene targets and gene/gene interactions, while other defects result in diabetic retinopathy or glaucoma. However, all of these insults as well as traumatic insults to the retina result in retinal remodeling. Retinal remodeling is a universal finding subsequent to retinal degenerative disease that results in deafferentation of the neural retina from photoreceptor input as downstream neuronal elements respond to loss of input with negative plasticity. This negative plasticity is not passive in the face of photoreceptor degeneration, with a phased revision of retinal structure and function found at the molecular, synaptic, cell, and tissue levels involving all cell classes in the retina, including neurons and glia. Retinal remodeling has direct implications for the rescue of vision loss through bionic or biological approaches, as circuit revision in the retina corrupts any potential surrogate photoreceptor input to a remnant neural retina. However, there are a number of potential opportunities for intervention that are revealed through the study of retinal remodeling, including therapies that are designed to slow down photoreceptor loss, interventions that are designed to limit or arrest remodeling events, and optogenetic approaches that target appropriate classes of neurons in the remnant neural retina.

Fig. 1

Human retina from a male patient with retinitis pigmentosa. Rod opsins reveal dramatic shortening of outer segments in a. Rod and LWS cone opsins are shown in phase one of retinal degeneration a and b. demonstrating photoreceptor stress through opsin delocalization from where it should normally be found in the outer segments: it now extends to the inner segments and the inner plexiform layer. Scale bar 10 μm

Fig. 2

In models of RP where rods and cones die simultaneously, bipolar cells lose dendrites and all iGluR/mGluR responsivity. In phase 0–1, rod bipolar cells downregulate GluR expression in the dendrites. In phase 1–2, rod and cone photoreceptor stress and death occur while dendritic modules are lost. In phase 3, wider retinal remodeling ensues, resulting in sprouting and formation of new axonal modules

Fig. 3

In models of RP where cones outlive rods, some bipolar cell dendrites switch targets. In normal rod bipolar cell architecture, dendrites from rod bipolar cells bypass cone pedicles. In phase 0–1, as in rod/cone dystrophies, rod bipolar^- cells downregulate GluR expression in the dendrites. In phase 1–2 with rod stress and death, dendritic modules are lost. In late phase 2/phase 3, some rod bipolar cells form sprouts that contact cone pedicles, making peripheral contacts on cone pedicles

Fig. 4

Retina from a human patient with advanced RP, illustrating pigmented bone spicules—accumulations of RPE pigment granules that derive from translocations of Müller cells, which alter the topology of the neural retina and cause the accumulation of pigment along clumps, lines, and grooves in the vertical axis of the neural retina. Scale bar 200 μm

Fig. 5

Neural emigration in a light damage model of retinal degeneration in rat. Taurine, glutamine, glycine::r, g, b mapping in a demonstrates Müller glia with glycinergic amacrine cells embedded in them passing outside of the retina through a break (box) in Bruch’s membrane. GABA, glycine, glutamate::r, g, b mapping in b demonstrates both GABAergic and glycinergic amaerine cells in addition to bipolar cells escaping from the neural retina into the choroid (arrows). Scale bar 90 μm

Fig. 6

Circuit diagram: rods provide sign-inverting input to ON bipolar cells via mGluR6-mediated synaptic connections. OFF bipolar cells are driven by cones through sign-conserving KA-mediated iGluRs, while ON bipolar cells are driven by cones through sign-inverting mGluR6-mediated synapses. Cone bipolar cells also synapse upon ganglion cells with sign-conserving AMPA-mediated iGluRs that define ON and OFF channels of information flow out of the retina. Information flow through the retina in humans during scotopic light levels is driven by rods and rod bipolar cells that piggyback onto intermediary amacrine cells, which shunt the flow of information to ON cone bipolar cells via sign-conserving gap junctions. Signaling to OFF cone bipolar cells occurs through sign-inverting glycinergic conventional synapses. In sum, a flash of light hyperpolarizes rod photoreceptors, and the network preserves the ON and OFF channel polarities. However, in cone-sparing RP seen in human and animal models, network flows arc compromised through the formation of pathological networks that generate conflicting signaling driven by the remaining cones. With cone degeneration, this cone signaling is eventually lost, and retinas are driven by signaling intrinsic to the remnant neural retinal amacrine and ganglion cells

Fig. 7

Imaging of human retina from late-stage RP. GABA, glycine, glutamate::r, g, b mapping in a reveals novel tufts of neuropil, termed microneuromas (box), with amacrine cells abutting Bruch’s membrane and the choroid. b Taurine, glutamine, glycine::r, g, b mapping of the same region demonstrates Müller cell revision and Müller cell seal formation (arrows), walling off the neural retina. Scale bar 90 μm

Fig. 8

Excitation recording with KA and AGB in horizontal sections through the bipolar cell layer of a 12-week old TgP347L rabbit retina visualized with glycine, AGB, glutamate::r, g, b mapping, showing that most (~82 %)of the bipolar cells have phenotypically switched from rod (diamonds) and ON-like BC (squares) responses to OFF-like BC (triangles) responses, revealing a fundamental molecular reprogramming of response states. Scale bar 60 μm

Fig. 9

Early-stage porcine P23H model of retinal degeneration. a Taurine, glutamine, glycine::r, g, b showing reduced photoreceptor outer segment length and early stages of Müller cell stress and alteration of molecular signatures (green/yellow), b GABA, glycine, glutamate::r, g, b of the same region showing normal-appearing OPL, IPL, and neuronal signatures. c Glycine immunohistochemistry demonstrating early retinal remodeling/sprouting in the glycinergic amacrine cell populations. d GABA, glycine, glutamate::r, g, b mapping shows dramatically truncated photoreceptor outer and inner photoreceptor segments with the glycine signal shown in c in the green channel, demonstrating remodeling events. Scale bar 30 μm

Fig. 10

a GABA, glycine, glutamate::r, g, b mapping of a 746-day-old GHL rabbit, showing a glial column with migration of amacrine and bipolar cells into the ganglion cell layer. Microneuroma (rectangle) has also formed distal to the heavily depleted inner nuclear layer, b Taurine, glutamine. glycine::r, g, b mapping of the same P347L rabbit tissue, revealing normal and abnormal Müller cells (box) in the mid-stage degenerate retina. Scale bar 30 μm

Fig. 11

a GABA, glycine, gluiamate::r, g, b mapping of a 900-day-old RCS rat retina. This image shows three columns of neuronal translocation from ONL to GCL in which bipolar and amacrine cells are migrating through the retinal axis, b GABA, glycine, glutamate::r, g, b mapping of a 630-day-old rdl mouse, demonstrating a column of neurons bridging the depleted inner nuclear layer with bidircctionally migrating amacrine and bipolar cells. c GABA, glycine, glutamale::r, g, b mapping of a 746-day-old GHL mouse, showing a glial column with migration of amacrine and bipolar cells into the ganglion cell layer. A microneuroma has also formed distal to the heavily depleted inner nuclear layer. Scale bar 60 μm

Fig. 12

a GABA, glycine, glutamate::r, g, b mapping in human geographic atrophy/AMD tissue demonstrates processes arising from both glycinergic and GABAergic amacrine cells (GABAergic processes extending into the outer plexiform layer in inset). These processes are the beginnings of microneuroma formation. b Taurine, glutamine, glutamate::r, g, b mapping demonstrates alterations in Müller cell signatures, notably an increase in the amount of taurine in subsets of Müller cells indicative of Müller cell stress (inset). Scale bar 90 μm

Fig. 13

Retina from a 23-month-old male DBA/2J mouse labeled for GABA, demonstrating aberrant GABAergic amacrine cell remodeling with new neurites projecting upwards into the outer plexiform layer. Scale bar 30 μm

Fig. 14

GABA, taurine, glutamate::r, g, b overlay on a TEM image of a peptidergic GABAergic amacrinc cell (asterisk) adjacent to a forming microneuroma in the RCS rat retina. Overlay CMP/TEM imaging enables connectomics and pathoconnectomics projects that elucidate precise, ultrastructural reconstruction of neuronal circuitry. Scale bar 6 μm