Neural remodeling in retinal degeneration
Introduction
The vertebrate retina is a tandem device: the photoreceptive, glutamatergic sensory retina drives the signal processing neural retina. Most retinal degenerations initially afflict the sensory retina and/or the RPE and many forms produce photoreceptor-depleted foci that expand and fuse, leading to extreme visual impairment or total blindness. Diverse sources of emerging data reveal negative plasticity in the remnant neural retina following loss of the sensory retina. The goal of this review is to draw together the lines of evidence; to detail the essential features of remodeling in retinal degenerations; to evaluate these processes in the context of known CNS plasticity and remodeling in response to challenges such as deafferentation. As a prototypical CNS assembly, the retina should be expected to remodel extensively in response to pathological stimuli. Alterations should be expected in the neural retina when photoreceptors degenerate. We will endeavour to show these expectations valid.
Though the notion of negative retinal remodeling induced by retinal degenerations is not new, it has not received much prior attention and certainly has not been integrated into schemata for retinal rescues. It can be argued that neural remodeling has been passively and actively neglected. A recent Medline search on “retinal degeneration” yielded ≈300 papers containing the words bipolar, horizontal, amacrine or Müller cells out of >13,000 articles retrieved. Less than 3% of relevant literature addresses the destinies of retinal neurons and glia after the death of their photoreceptor partners. This is partly due to the essential transparency of remodeling. In the absence of photoreceptor drive, remodeling is undetectable in vivo and histological methods such as routine light microscopy are insensitive to the early responses of neurons to photoreceptor stress and death. The vast majority of scientific papers dealing with the fate of the neural retina during and after photoreceptor degeneration have focused on numerical cell survival, largely neglecting classical and advanced methods for neuronal visualization. Given our current knowledge regarding the molecular deconstruction of photoreceptors during challenge or degeneration (John et al., 2000; Rex et al., 2002), we might profitably inquire of the morphological and biochemical integrities of the ≈55–60 classes of neurons that form a mammalian retina. Confocal microscopy, advanced immunocytochemical techniques, and quantitative molecular phenotyping have opened new windows on remodeling. Its pervasiveness emerges as irrefutable. Even so, various recent media still present the view that the neural retina is either refractory to photoreceptor loss or that changes may be minimal (Scarlatis, 2000; Chow et al., 2002; Gekeler and Zrenner, 2002; Margalit et al., 2002; Zrenner, 2002).
Degeneration of the sensory retina is often accompanied by early changes in circuitry of the neural retina (Wong, 1997; Banin et al., 1999; Peng et al., 2000; Strettoi and Pignatelli, 2000; Aleman et al., 2001; Strettoi et al (2002), Strettoi et al (2003)). These changes do not abate, but rather devolve to a protracted phase of negative remodeling of neuronal and glial elements in the remnant neural retina (Marc et al., 2001; Ren et al., 2001; Jones et al (2002), Jones et al (2003a); Sullivan et al., 2003). The key trigger seems to be the loss of cone photoreceptors. Remodeling involves three levels of restructuring in the neural retina: (1) neuronal death; (2) migration of cells; (3) rewiring. These are not trivial or collectively rare events, though visualizing them requires selective detection technologies. Remodeling potentially corrupts spatial processing and may even transform retinas into self-signaling neuronal assemblies with little ability to provide “proper” signal throughput as gauged by normal assemblies of visual circuits. Such changes may render many cell and bionic implant rescue strategies unfeasible. Beyond this, remodeling may constrain windows of opportunity for genetic rescues or molecular retinal maintenance. The mechanisms triggering remodeling are unknown, but it is a general feature of mammalian neural retinas challenged by sensory deafferentation effected by a range of photoreceptor degenerations. Our theme is that the mammalian retina is similar to other areas of the central nervous system (CNS) in its response to deafferentation on molecular, cellular and systems levels. Both retina and CNS display atrophy, apoptosis, reshaping of axonal and dendritic fields, revision of synaptic connectivity and efficacy that alter the signal processing attributes of entire pathways, alterations in gene expression, and glial transformations. Remodeling in the CNS is often guided by remnant synaptic inputs, while the retina becomes a system unto itself. Retinal remodeling has three implications we wish to emphasize. 1. Remodeling exposes the cryptic, incipient plasticity of the normal mammalian retina. 2. Remodeling challenges cellular and implant rescue strategies. 3. Remodeling may enable experimental revision of the remnant retina.
Neural remodeling in the degenerating mammalian retina follows a stereotyped sequence of events after photoreceptor degeneration. As this review will examine many of these events in some detail, it is profitable to start with an overview of remodeling. The remodeling scenario is outlined in Fig. 1, using the human retina as an exemplar, recalling that mammalian retinas used as experimental surrogates are virtually identical to >90% the human retina in terms of cone density, circuitry, and the molecular signatures of individual cell types. Retinal degenerations are of three basic forms: rod-initiated, cone-initiated, and debris initiated. We will use the common rod-initiated RP-like process for an outline and note key deviations in certain models where necessary.
Phase 0: The normal retina. The retina represents separate transport compartments bounded by cellular seals. The sensory retina is composed of photoreceptor cells and is internally compartmentalized by high-resistance tight junction arrays formed distally at the basolateral RPE margins and high-resistance intermediate junctions arrays formed proximally by Müller cell apical microvilli. The latter constitutes a diffusion barrier perforated by photoreceptor inner limbs: the perinuclear soma, nucleus, axon and synaptic terminal. The RPE is the blood retinal barrier for the outer limbs of photoreceptors: myoids, ellipsoids and outer segments. The neural retina is a bounded entirely by high-resistance intermediate junction seals of the Müller cells: distally at the apical microvilli, proximally at the Müller cell foot pieces and internally at vessels invested by Müller cell processes. This scheme functionally isolates the extracellular sensory transduction compartment of photoreceptors from their extracellular neural synaptic compartment, similar to hair cells and other sensory cell arrays. Within the sensory retina, the RPE and Müller cells regulate ionic transport, metabolite transport, fluid transport, retinoid transport, and outer segment turnover. Within the neural retina, Müller cells specifically regulate extracellular K+, GABA and glutamate levels; provide glutamine for glutamate synthesis; regulate extracellular volume (likely via anion flux and taurine transport); and provide for carbon skeleton recycling and redistribution.
Phase 1: Rod degeneration. Whether triggered by malfunction or insufficiency of specific proteins, degenerating rods display progressive decreases their ability to produce outer segments. The rate of synthesis lags RPE phagocytosis and outer segments shorten. Though the mechanisms of photoreceptor stress and forms of apoptosis may be debated, rods with shortened outer segments are at risk. Most rods are fated to die and move through stressed, deconstructed, irreversibly stressed, and apoptotic stages. Some rods may escape stress and enter the neural retina as survivor rods, but this appears to be rare. The details of cone stress during this phase are not clear, but the subretinal space is compressed and cone outer segments are truncated. Initial changes in the neural retina are dramatic but transparent to simple histological examinations. During initial stress and rod deconstruction, rod neurites sprout and enter the inner retina, extending to the ganglion cell layer in some cases and expressing rhodopsin. In late phase 1 or early phase 2, rods may retract neurites and remnant presynaptic terminals prior to death.
Phase 2: Cone degeneration. When rod outer segments are lost, plasma membrane rhodopsin levels in rod inner segments rise and the rate of rod death increases. Collapse of the subretinal space parallels the ablation of cone outer segments and remodeling of the inner segment. Cone deconstruction includes redistribution of cone opsins to inner segments, changes in expression of key proteins, and perhaps transient extension of axons into the neural retina. Cones begin to die, likely due to multiple stressors, but death may be accelerated by migration of activated microglia into the sensory retina. Elaboration of a fibrotic distal seal by Müller cells, some of which show nuclear translocation into the outer nuclear layer, entombs the remaining cones. Initial remodeling of the neural retina begins as rod and cone bipolar cells retract their dendrites and revise their expression of synaptic signaling receptor proteins. The rod-targeted axon terminal fields of horizontal cells undergo retraction and the cone-targeted horizontal cell somas hypertrophy and extend new neurites into the inner plexiform layer. Every bipolar and horizontal cell appears to be remodeled. Though a fraction of bipolar cells dies at this stage, the changes are quantitatively invisible by routine histological analysis.
Early phase 3: Progressive neurite remodeling. The loss of the sensory retina completes the deafferentation of the neural retina and the Müller cell seal becomes compacted. The seal is irreversibly bound to and invests the neural retina. Müller cell hypertrophy, in part due to up-regulation of intermediate filament synthesis, forms large columns that segment the retina. Neurons of the inner plexiform layer begin to remodel, with new neurites from all cell types appearing in the inner nuclear layer, forming patchy foci in the remnant outer plexiform layer. Global neuronal cell death is statistically detectable.
Middle phase 3: Global remodeling. Global remodeling includes concurrent neuronal death, cell migration, and rewiring via ectopic fascicle evolution and formation of ectopic synaptic microneuromas. Neuronal death shows no bias; all cell types are vulnerable. The rate is also variable and appears partially dependent on the speed and coherence of cone loss in phase 2. Neuronal migration includes eversion of amacrine cells to the distal margin of the retina and inversion of bipolar and amacrine cells to the ganglion cell layer, perhaps guided by Müller cell surfaces. Bundles of mixed neurites from all cell types course through the retina at all levels, most graphically in the remnant outer plexiform layer just proximal to the glial seal. Microneuromas contain synaptic terminals of all types of neurons, including bipolar cell ribbon synapses and conventional synapses of GABAergic and glycinergic amacrine cells. All neurons appear to preserve their normal basic molecular signatures. New synaptic connections are abundant.
Late phase 3: Plateau remodeling. Basic remodeling processes persist. Neuronal death continues and can significantly deplete the inner nuclear and ganglion cell layers, with Müller cells partially filling the space. Neurite fascicles and microneuromas may regress as neuronal cell death depletes the retina. The inner plexiform layer becomes thinner. The optic fiber layer can become thinned and ganglion cell layer vessels migrate into the retina. Preretinal membranes and new extracellular matrices are formed. In some diseases, progressive RPE alterations are evident, including cell death, elaboration of columns of apical processes extending deep into the remnant neural retina, and migration of some survivor RPE cells into the retina, lining retinal vessels.
Different initial scenarios for cone- and debris-initiated retinal degenerations. Cone-initiated diseases may simply reverse the order of photoreceptor loss. Phase 1 would encompass cone stress and apoptosis, followed by phase 2 ablation of the outer nuclear layer via bystander-effect loss of rods. This excludes those cone dystrophies in which rods are spared. Cone–rod dystrophies and debris-initiated diseases may display overlapping phases 1 and 2. Debris-initiated retinal degenerations are largely those in which RPE function is directly or secondarily compromised, resulting in an inability to internalize outer segments and accumulation of debris in the subretinal space. Cumulative stresses such as lipid oxidation, metabolite deprivation, microglia/macrophage activation may lead to a relatively coherent loss of rods and cones. However, after sensory deafferentation, neural remodeling appears to follow the same phase 3 profiles.
Section snippets
Human retinal degenerations initiated by rod, cone and RPE defects
Human retinal degenerations largely originate in the sensory retina and its adjacent transport tissues, the RPE and choroid. They are diversely sorted by clinical phenotypes, affected gene, protein function and malfunction, and cellular association (Daiger and Sullivan, 2003). With respect to ultimate photoreceptor loss, inherited disorders form a continuum (Deutman and Hoyng, 2001; Rivolta et al., 2002). Some cone dystrophies (COD) exist as isolated photopic dysfunction, with preservation of
Rod and cone death patterns in retinal degenerations
Significant effort is now being expended to determine why and how photoreceptors die in retinal degenerations and what environmental factors might impact the speed and scope of cell death (Remé et al., 1998; Hao et al., 2002). Many of these details clearly lie outside the scope of this review, but the initiators, secondary stressors, and durations of stress prior to photoreceptor death likely shape the natures and extents of early remodeling defects.
Developmental plasticity
Prior to exploring reactions of the mature neural retina to sensory deafferentation, it is useful to review evidences of plasticity in the retina. Circuit assembly in the mammalian retina involves significant postnatal refinement, including improved high spatial frequency cutoffs of retinal ganglion cells at about pnd 30 in cats (Rusoff and Dubin, 1977). There is increasing evidence that light history impacts maturation. In a remarkable study, Ikeda and Wright (1976) demonstrated that the
Deprivation and deafferentation-induced remodeling in the CNS
As we are about to consider remodeling in the retina, as brief review of CNS remodeling is in order. The mammalian CNS remodels during development and learning, as well as in response to injury or disease. Plastic responses produced by CNS neurons in association with learning and memory, e.g. changes in the numbers of dendritic spines (Sorra and Harris, 2000), are compelling examples of the flexibility of neuronal circuits. Altered visual experience can induce compensatory axonal sprouting
Systems expressing early remodeling of neural retina
Only a few model systems have been carefully examined for evidence of early remodeling, but the data are unequivocal: even at early stages of photoreceptor stress and deconstruction, the neural retina reacts with bipolar and horizontal cell remodeling. The most extensive analysis has been carried out in the rd1 mouse, but similar phenomena have been observed in the rd10 mouse, Crx−/− mouse, FVB/N mouse, RCS rat, and P347L transgenic pig. Early remodeling is transparent to conventional
Anatomical evidence for late remodeling in human retinal degenerations
The earliest data suggesting that advanced retinal degenerations triggered more severe defects than merely the loss of part or all of the sensory retina arose from standard histological surveys of retinitis pigmentosa tissue. The advent of animal models has driven many of these studies from recent memory, leaving many with the impression that loss of the sensory retina is the only significant defect arising in retinal degenerations. The true status of the neural retina has not been better
Basic mammalian pathways
Even in rod-rich mammalians, cone circuitry dominates (Strettoi et al., 1994). Of the ≈55–60 classes of retinal elements that constitute a generalized mammalian retina (MacNeil et al (1999a), MacNeil et al (1999b); Masland (2001a), Masland (2001b); Marc and Jones, 2002; Rockhill et al., 2002), all but five are predominantly or exclusively driven by cones. The mammalian rod pathway is composed of but two purely rod-driven neurons (rod bipolar cells and horizontal cell axon terminals functioning
Implications of remodeling for rescue strategies
The clinical relevance of remodeling in retinal blinding diseases is substantial. The fundamental strategies of subretinal and epiretinal prosthetic implants, photoreceptor transplants, stem cell therapies, gene rescue therapies, survival factor treatments and combinations thereof are based upon the hope that the neural retina remains viable after extensive photoreceptor degeneration; that the neural retina should act as a platform to accept donor cells and quantitatively respond to
The future: retinal plasticity and remodeling
The scope of true physiological plasticity in the adult mammalian retina is unknown, but given our knowledge of the extent of network adaptation and structural revision displayed by non-mammalian retinas, extensive functional plasticity in terms of synaptic strengths or even structural changes may be expected. Further, the processes invoked in early development of retinal lamination (Johnson et al., 1999), spatial patterning (Reese and Galli-Resta, 2002) and functional activity (Tian and
Acknowledgements
The preparation of this review was funded in part by NEI R01 EY02576 (RM), TeleThon Project E0833 (ES) and NEI R01 EY12654 (ES). Our thanks to many colleagues who advised us on revisions. The remaining errors are ours alone.
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