Chapter 10 - Retinal ganglion cell dendrite pathology and synapse loss: Implications for glaucoma
Section snippets
Does Dendritic Pathology Contribute to Vision Loss in Glaucoma?
During normal visual processing, retinal ganglion cell (RGC) dendrites receive synaptic inputs from bipolar and amacrine cells in the inner plexiform layer. This information is integrated, processed, and sent via RGC axons in the optic nerve to visual centers in the brain (Masland, 2012). The structural integrity of dendrites is essential for vision. Dendrites allow communication between RGCs and other retinal neurons via synapses. Furthermore, dendrites integrate and propagate input signals to
Morphological Diversity of RGC Dendrites: An Embarrassment of Riches
Newly born RGCs initiate an axon that grows along the nerve fiber layer lining the innermost surface of the retina, then exits the eye via the ONH, and extends into the optic nerve proper to reach targets in the brain (Bao, 2008, Haupt and Huber, 2008). As RGC axons enter the brain, dendrites begin to grow from the cell soma extending through the inner plexiform layer to form synapses with bipolar and amacrine cell processes (Choi et al., 2010, Holt, 1989). Primary dendrites then branch to
Axonal Injury Triggers Pathological Changes in RGC Dendrites
Changes in RGC dendrites have been historically perceived as anecdotal or intriguing at most. Indeed, very few studies on RGC dendritic alterations in models of optic nerve damage were published before 2010. Among these were the pioneering work by Weber and colleagues describing early structural abnormalities in RGC dendrites in a nonhuman primate model of chronic IOP elevation (Weber et al., 1998). In this study, parasol cells in glaucomatous eyes showed a significant reduction in dendritic
Mechanisms That Regulate Dendrite and Synapse Stability
Despite the fact that dendritic and synaptic defects are likely to have devastating consequences on neuronal function and survival, the mechanisms that regulate RGC dendrite degeneration in glaucoma are vastly unknown. A better understanding of the molecular pathways that regulate dendritic stability or loss is critical for the development of targeted therapies to maintain or enhance RGC connectivity and function. The next sections describe new findings on molecular pathways that regulate RGC
Conclusions and Future Directions
In recent years, there has been a tangible increase in the number of studies investigating RGC dendritic abnormalities triggered by axonal injury. Emerging data indicate that damage to RGC axons, by ocular hypertension or acute insults, triggers rapid, and marked dendritic modifications. Most studies agree that the primary changes involve dendritic retraction, characterized by a reduction in dendritic field area, process length, and arbor complexity. The consensus is that these dendritic
Acknowledgments
This work was supported by grants to A.D.P. from the Canadian Institutes of Health Research (CIHR). We thank Dr. Timothy E. Kennedy for comments on the manuscript, and Mr. James Correia for assistance with the figure.
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Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering
2023, Molecular Aspects of MedicineSystemic treatment with 7,8-Dihydroxiflavone activates TtkB and affords protection of two different retinal ganglion cell populations against axotomy in adult rats
2021, Experimental Eye ResearchCitation Excerpt :In adult rats, Brn3a is expressed by the vast majority of the RGC population (≈96%) (Nadal-Nicolás et al, 2014, 2015a, 2015b) (Brn3a+RGCs) responsible for image-forming visual functions, while melanopsin is expressed in a small subset of RGCs (m+RGCs; ≈2.5%) named intrinsically photosensitive RGCs (Galindo-Romero et al., 2013a; Nadal-Nicolás et al., 2014) and are mainly responsible for nonimage-forming visual functions (Vidal-Villegas et al., 2020). Previous studies, have documented that these markers are expressed long term after retinal injury (Agudo-Barriuso et al., 2016; Nadal-Nicolás et al, 2015a, 2015b; Sánchez-Migallón et al, 2011, 2016), and this is important because injured RGCs undergo changes in their morphology, physiological properties and gene expression that renders their identification difficult (Agostinone and Di Polo, 2015; Agudo-Barriuso et al., 2013; Agudo et al, 2008, 2009; Chidlow et al., 2005). The flavonoid, 7,8-Dihydroxyflavone (DHF) is a potent mimetic of the neurotrophin brain derived neurotrophic factor (BDNF) (Barde et al., 1982) and exhibits neuroprotective properties in several CNS degenerative diseases through activation of the tropomyosin related kinase B (TrkB) receptor through its phosphorylation, internalization and the consequent initiation of downstream survival pathways (Emili et al., 2020; Jang et al., 2010).
Adaptive responses to neurodegenerative stress in glaucoma
2021, Progress in Retinal and Eye ResearchCitation Excerpt :An early marker of progression in rodents is degradation of anterograde axonal transport from the retina to central brain projection sites, followed by disassembly of the myelinated axon and degeneration of post-synaptic targets (Crish et al., 2010; Calkins and Horner, 2012; Calkins, 2012; Crish and Calkins, 2015). In the retrograde direction, RGC dendritic arbors lose complexity as excitatory synapses are eliminated in a complement-dependent process (Agostinone and Di Polo, 2015; Berry et al., 2015; Williams et al., 2016). Pruning due to acute axonal injury in rodents involves loss of activity from mammalian target of rapamycin (or mTOR), which may have bearing in human glaucoma (Agostinone et al., 2018).
Discovery and clinical translation of novel glaucoma biomarkers
2021, Progress in Retinal and Eye ResearchCitation Excerpt :Of course, although the eye is the most accessible organ for direct, high-resolution imaging, we believe that MRI data will continue to contribute to deepening our understanding in experimental models, even if it will not be frequently used for routine clinical imaging of glaucoma patients. The inner plexiform layer (IPL), comprising dense connections between bipolar cell axons, amacrine cells, and ganglion cell dendrites, is another prime site for investigating both glaucoma pathophysiology and biomarker development (Agostinone and Di Polo, 2015). A number of functional and molecular pathways implicated in glaucoma have been localized to the IPL synapses (Stevens et al., 2007; Howell et al., 2011; Agostinone et al., 2018), and RGC dendrite degeneration or remodeling is observed early in disease in animal models, and particularly may be detected earliest in “OFF” RGCs, the dendrites of which are in the outermost lamina of the IPL (Della Santina et al., 2013; El-Danaf and Huberman, 2015; Ou et al., 2016; Puyang et al., 2017) (see Fig. 5).