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Glaucoma is a neurodegenerative disease characterised by progressive damage to the retinal ganglion cells (RGCs), the output neurons of the retina. RGCs are a heterogenous class of retinal neurons which can be classified into multiple types based on morphological, functional and genetic characteristics. This review examines the body of evidence supporting type-specific vulnerability of RGCs in glaucoma and explores potential mechanisms by which this might come about. Studies of donor tissue from glaucoma patients have generally noted greater vulnerability of larger RGC types. Models of glaucoma induced in primates, cats and mice also show selective effects on RGC types - particularly OFF RGCs. Several mechanisms may contribute to type-specific vulnerability, including differences in the expression of calcium-permeable receptors (for example pannexin-1, P2X7, AMPA and transient receptor potential vanilloid receptors), the relative proximity of RGCs and their dendrites to blood supply in the inner plexiform layer, as well as differing metabolic requirements of RGC types. Such differences may make certain RGCs more sensitive to intraocular pressure elevation and its associated biomechanical and vascular stress. A greater understanding of selective RGC vulnerability and its underlying causes will likely reveal a rich area of investigation for potential treatment targets., (© 2019 Optometry Australia.)

Analysis of how retinal ganglion cells change in retinal degeneration is critical for evaluating the potential of photoreceptor restorative therapies. Immunocytochemistry in combination with image analysis provides a way for quantifying not only the density of ganglion cells during disease, but also information about their morphology and an evaluation of excitatory and inhibitory synaptic inputs. Here, we describe how indirect immunofluorescence can be used in retinal whole mounts to obtain information about ganglion cells in retinal degeneration.

Inherited retinal degeneration such as retinitis pigmentosa (RP) is associated with photoreceptor loss and concomitant morphological and functional changes in the inner retina. It is not known whether these changes are associated with changes in the density and distribution of synaptic inputs to retinal ganglion cells (RGCs). We quantified changes in ganglion cell density in rd1 and age-matched C57BL/6J-(wildtype, WT) mice using the immunocytochemical marker, RBPMS. Our data revealed that following complete loss of photoreceptors, (∼3months of age), there was a reduction in ganglion cell density in the peripheral retina. We next examined changes in synaptic inputs to A type ganglion cells by performing double labeling experiments in mice with the ganglion cell reporter lines, rd1-Thy1 and age-matched wildtype-Thy1. Ribbon synapses were identified by co-labelling with CtBP2 (RIBEYE) and conventional synapses with the clustering molecule, gephyrin. ON RGCs showed a significant reduction in RIBEYE-immunoreactive synapse density while OFF RGCs showed a significant reduction in the gephyrin-immmunoreactive synapse density. Distribution patterns of both synaptic markers across the dendritic trees of RGCs were unchanged. The change in synaptic inputs to RGCs was associated with a reduction in the number of immunolabeled rod bipolar and ON cone bipolar cells. These results suggest that functional changes reported in ganglion cells during retinal degeneration could be attributed to loss of synaptic inputs., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Ganglion cells are the output neurons of the retina and are known to remodel during the subtle plasticity changes that occur following the death of photoreceptors in inherited retinal degeneration. We examine the influence of retinal eccentricity on anatomical remodelling and ganglion cell morphology well after photoreceptor loss. Rd1 mice that have a mutation in the β subunit of phosphodiesterase 6 were used as a model of retinal degeneration and gross remodelling events were examined by processing serial sections for immunocytochemistry. Retinal wholemounts from rd1-Thy1 and control Thy1 mice that contained a fluorescent protein labelling a subset of ganglion cells were processed for immunohistochemistry at 11 months of age. Ganglion cells were classified based on their soma size, dendritic field size and dendritic branching pattern and their dendritic fields were analysed for their length, area and quantity of branching points. Overall, more remodelling was found in the central compared with the peripheral retina. In addition, the size and complexity of A2, B1, C1 and D type ganglion cells located in the central region of the retina decreased. We propose that the changes in ganglion cell morphology are correlated with remodelling events in these regions and impact the function of retinal circuitry in the degenerated retina.

Retinitis pigmentosa refers to a family of inherited photoreceptor degenerations resulting in blindness. During and after photoreceptor loss, neurons of the inner retina are known to undergo plastic changes. Here, we have investigated in detail whether ganglion cells are altered at late stages of degeneration, well after the total loss of photoreceptors. We used mice, rd1-Thy1, that carry a mutation in the β-subunit of phosphodiesterase 6 and a fluorescent protein that labels a subset of ganglion cells and B6-Thy1 control mice. Retinal wholemounts from mice aged 3-11 months were processed for immunohistochemistry and analyzed. Ganglion cells were classified based on soma area, dendritic field size, and branching of dendrites. The dendritic fields of some ganglion cells were further analyzed for their length, area and quantity of branching points. There was a decrease in size and level of branching of A2, B1, and D type ganglion cells in the degenerated retina at 11 months of age. In contrast, C1 ganglion cells remained unchanged. In addition, there was a shift in the proportion of ganglion cells ramifying in the different layers of the inner plexiform layer. Careful analysis of the dendrites of ganglion cells revealed some projecting to new, more distal regions of the inner plexiform layer. We propose that these changes in ganglion cell morphology could impact the function of individual cells as well as the retinal circuitry in the degenerated retina., (Copyright © 2013 Wiley Periodicals, Inc.)

Retinal prostheses aim to restore vision to patients who are blind from photoreceptor diseases such as Retinitis Pigmentosa (RP). All implants target the neural cells in the inner retina, the retinal ganglion cells (RGCs). Our research focuses on further understanding the disease process of RP during mid to late stages when total loss of photoreceptors has occurred and significant remodeling of inner retinal neurons has taken place. We have used a novel transgenic mouse, Rd1-FTL, to observe different degenerative stages of RP. Notably, in the aged retina we have evidence that there was gross inner retinal remodeling as well as glial dysfunction that occurred in confined regions in the central retina that worsened overtime. Consequently, the timing of implantation and location of the prosthesis both need to account for the state of the retina at different stages in the disease process.

Purpose: Retinitis pigmentosa (RP) is a blinding disease caused by the degeneration of photoreceptors. To further understand the process of degeneration in RP, the authors have traced activation patterns associated with rod and cone photoreceptor degeneration in a mouse model of RP METHODS: The authors used a double-mutant mouse, Rd-FTL, which contains a natural mutation, rd1, affecting the rod photoreceptors and an axon-targeted beta-galactosidase reporter system, which is under the regulation of the promoter of the c-fos gene. These mice allowed the authors to trace degeneration-related activity that corresponded to rod and cone death., Results: The authors traced cell death-associated activation in both rods and cones, allowing them to accurately determine the time course of cone degeneration in these mice. In the analysis of downstream activation patterns in the inner retina, they found that amacrine and ganglion cells maintain their photopic light-related activation until at least the initiation of cone degeneration. These cell populations then show increased activity during the peak time of cone cell degeneration. The authors also examined light-regulated functional activation of a subclass of amacrine cells, the dopaminergic amacrine cells. These cells showed light-induced functional activation after rod photoreceptor death and until the period of cone photoreceptor death, suggesting that they can be regulated by cone photoreceptors alone., Conclusions: These findings have helped to accurately trace the periods of photoreceptor degeneration in this model of RP and show that correct light-regulated inner retinal activation is maintained until the time of cone degeneration.

Direction-selective (DS) ganglion cells of the mammalian retina have their dendrites in the inner plexiform layer (IPL) confined to two narrow strata. The same strata are also occupied by the dendrites of cholinergic amacrine cells which are probably presynaptic to the DS ganglion cells. GABA is known to play a crucial role in creating DS responses. We examined the types of GABAA receptors expressed by the cholinergic amacrine cells and also those expressed by their presynaptic and postsynaptic neurons, by applying immunocytochemical markers to vertical sections of rat retinas. Double-labelling experiments with antibodies against choline acetyltransferase (ChAT) and specific antibodies against different GABAA receptor subunits were performed. Cholinergic amacrine cells seem to express an unusual combination of GABAA receptor subunits consisting of alpha 2-, beta 1-, beta 2/3-, gamma 2-, and delta-subunits. Bipolar cells, which could provide synaptic input to the DS circuitry, were stained with antibodies against the glutamate transporter GLT-1. The axon terminals of these bipolar cells are narrowly stratified in close proximity to the dendritic plexus of displaced cholinergic amacrine cells. The retinal distribution of synaptoporin, a synaptic vesicle associated protein, was studied. Strong reduction of immunolabelling was observed in the two cholinergic strata. The anatomical findings are discussed in the context of models of the DS circuitry of the mammalian retina.

Abstract: The vertebrate retina receives histaminergic input from the brain via retinopetal axons that originate from perikarya in the posterior hypothalamus. In the nervous system, histamine acts on three G-protein-coupled receptors, histamine receptor (HR) 1, HR2 and HR3. In order to look for potential cellular targets of histamine in the mouse retina, we have examined the retina for the expression of histamine and the presence of these three receptors. Consistent with studies of retina from other vertebrates, histamine was only found in retinopetal axons, which coursed extensively through the ganglion cell and inner plexiform layers. mRNA for all three receptors was expressed in the mouse retina, and immunohistochemical studies further localized HR1 and HR2. HR1 immunoreactivity was observed on dopaminergic amacrine cells, calretinin-positive ganglion cells and axon bundles in the ganglion cell layer. Furthermore, a distinct group of processes in the inner plexiform layer was labeled, which most likely represents the processes of cholinergic amacrine cells. HR2 immunoreactivity was observed on the processes and cell bodies of the primary glial cells of the mammalian retina, the Müller cells. This distribution of histamine and its receptors is consistent with a brain-derived source of histamine acting on diverse populations of cells in the retina, including both neurons and glia. [Copyright &y& Elsevier]