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Show STATE OF THE ART Dendritic and Synaptic Protection: Is It Enough to Save the Retinal Ganglion Cell Body and Axon? Junie Barbara Morquette, MSc and Adriana Di Polo, PhD Abstract: Glaucoma and other optic neuropathies have been traditionally viewed as diseases of the optic nerve that lead to retinal ganglion cell (RGC) degen-eration. Accordingly, the primary aim of neuropro-tective strategies has been to preserve RGC axons and soma. RGCs are complex and highly polarized central neurons, and their pathologic response in disease is likely to be an integration of signals from all cellular compartments-axons, soma, dendrites, and synaptic contacts. We focus on the role of dendrites and dendritic spines in normal neuronal function, neuro-logic disorders, and glaucoma. The need to un-derstand the mechanisms underlying RGC dendrite and synapse degeneration in glaucoma and other optic neuropathies is compelling, as it may provide insight into novel therapeutic strategies to prevent vision loss. (J Neuro-Ophthalmol 2008;28:144-154) RETINAL GANGLION CELL NEUROPROTECTION IN GLAUCOMA: RATIONALE, STRATEGIES, AND CURRENT LIMITATIONS Glaucoma is a group of diseases characterized by progressive optic nerve degeneration that leads to visual field loss and irreversible blindness. A common character-istic of all types of glaucoma and other optic neuropathies is the death of retinal ganglion cells (RGCs) (1). When there is substantial loss of RGCs, the patient experiences pro-gressively worsening vision. Visual loss usually starts in the periphery and advances to involve the fixational area with devastating consequences for the patient's quality of life. Department of Pathology and Cell Biology and Groupe de Recherche sur le Systeme Nerveux Central, University of Montreal, Montreal, Quebec, Canada. Address correspondence to Adriana Di Polo, PhD, Department of Pathology and Cell Biology, Universite de Montreal, 2900, Boulevard Edouard-Montpetit, Pavilion Principal, Room N-535, Montreal, QC H3T 1J4, Canada; E-mail: adriana.di.polo@umontreal.ca The direct cause of glaucoma is unknown, but several major risk factors have been identified (2). For example, the incidence of glaucoma increases with age and startlingly high rates of disease are found in elderly individuals (3). Elevated intraocular pressure is another major risk factor in glaucoma. Open-angle and angle-closure glaucoma, the most common forms of the disease, are often associated with high intra-ocular pressure. The current standard therapy for glaucoma is to lower eye pressure using medications and/or surgery. A significant proportion of patients, however, continue to experience visual loss despite responding well to pressure-lowering medications (4-7). Therefore, current therapeutic strategies for glaucoma may be insufficient, and new ap-proaches to slow down disease progression are needed. Neuroprotection has been considered an alternative strategy to keep neurons alive in neurologic diseases. In the context of optic neuropathies, neuroprotection is often thought of as a therapy to prevent the death of RGCs. Many neuroprotective strategies that aim to saving RGCs have been tested in the laboratory using a variety of optic nerve injury models. Supplementation of neurotrophic factors (8-19) and activation of their downstream signaling molecules (20-23), inhibition of pro-apoptotic molecules (24-30), and prevention of glutamate receptor activation (31-33) are some examples of successful RGC neuro-protection based on laboratory evidence. It has been suggested that glaucoma and possibly other optic neuropathies are axogenic diseases, character-ized first by the degeneration of RGC axons in the optic nerve followed by progressive loss of cell bodies (34). Based on this theory, the assessment of neuroprotection in the laboratory has focused on the quantification of remain-ing axons or cell bodies, or both, after optic nerve injury (Fig. 1). This approach, however, is only a partial mor-phologic assessment of neuronal viability, mainly because RGCs are central nervous system neurons with a complex structure comprising more than just cell bodies and axons. Like other sensory neurons, RGCs follow the rules of func-tional polarity and are endowed with specialized structures that allow them to communicate with other neurons in 144 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Retinal Ganglion Cells J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Retinal Ganglion Cell Bodies In Rat Retina Flat Mount Retinal Ganglion Cell Axons In Rat Optic Nerve FIG. 1. A. Retinal ganglion cell (RGC) bodies in flat-mounted rat retina after application of retrograde tracer Fluorogold to the superior colliculus. B. RGC axons in cross-section of Epon-embedded rat optic nerve, light microscopy. Scale bars: 50 |xm. the retina and brain. The theory of functional polarity, first documented by Santiago Ramon y Cajal in his classical neuroanatomy study "The Histology of the Nervous Sys-tem in Man and Vertebrates" (35) states that information in a neural circuit flows from the dendrites and cell soma to a single axon that ends in a specialized synaptic terminal (Fig. 2). The dendrites and soma are the receptive struc-tures; the axon is the output structure. The final response of EYE OPTIC NERVE BRAIN Axon Dendrites Cell Body Spine Synaptic terminals FIG. 2. A. RGC response to visual stimulation is the result of signal integration from all cellular compartments: dendrites, cell body, axon, and synaptic terminals. B-D. Confocal images of different cellular compartments of an adult mouse RGC expressing yellow fluorescent protein. Images were taken from three different focal planes in the z-axis to show an RGC body (B, arrowhead), axon (C, arrowhead) and elaborate dendritic tree (D). Scale bars: 50 |xm. 145 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Morquette and Di Polo a neuron and its neural activity outcome are the result of signal integration from all of the cellular compartments: dendrites, cell body, axon, and synaptic terminals. In the retina, RGC dendrites (Fig. 3) receive their synaptic inputs from bipolar and amacrine cells in the inner plexiform layer (IPL). The information is then integrated, processed, and sent via the optic nerve to visual centers in the brain. Dendrites are indispensable components of RGC structure, connectivity, and function. We focus here on the role of dendrites and dendritic spines in normal neuronal function and how these struc-tures are affected in physiologic conditions such as normal development and aging and in neurodegenerative disorders including glaucoma. We also emphasize the importance of Rod Cone Rod OFF Bipolar cell 0 Amacrine cell Horizontal cell ON Bipolar cell • OFF Ganglion cell OFF ON Photoreceptors outer segments Outer nuclear layer Outer plexiform layer Inner nuclear layer Inner plexiform layer ON Ganglion cell Ganglion cell layer FIG. 3. Synaptic input of RGCs. In the mature retina, the dendrites of OFF RGCs arborize in sublamina a where they receive input from OFF bipolar cells, whereas the ON RGC dendrites are confined to sublamina b where they contact ON bipolar cells. The visual information is integrated by RGCs, processed, and sent via their axons in the optic nerve to centers in the brain. 146 © 2008 Lippincott Williams & Wilkins Retinal Ganglion Cells J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 further characterizing established and novel neuroprotec-tive strategies to ensure that all RGC compartments are protected with the goal of preserving neural function and ultimately vision. DENDRITES: EVER CHANGING TREES Dendrites are major determinants of how neurons integrate and process incoming information and, as such, play a vital role in the functional properties of neural circuits. Dendrites receive synaptic inputs on their shaft or on small protuberances known as dendritic spines and then integrate and transmit this information to the cell soma. As the nervous system develops, individual neurons undergo significant morphologic changes that encompass dendritic outgrowth, arborization, and synaptogenesis. Dendrites are extremely dynamic during development, expanding and retracting actively shortly after axon formation in response to intrinsic and environmental cues (36,37). The factors that regulate RGC dendritic growth and patterning during development have been the subject of excellent reviews (38,39). Neurotrophic factors and neuronal activity are important during development of RGC dendritic arboriza-tion. For example, brain-derived neurotrophic factor (BDNF) has emerged as a key neurotrophin in the reg-ulation of RGC dendritic morphology. In the developing Xenopus retina, there is an inverse correlation between the BDNF levels in the retina and the complexity of RGC dendritic arbors (40). Administration of exogenous BDNF in the retina at the onset of dendritic development resulted in smaller and less complex RGC dendritic processes. In contrast, reduction of retinal BDNF levels, by application of a neutralizing BDNF antibody, led to increased dendrite elaboration and arbor complexity. Interestingly, adminis-tration of BDNF in the optic tectum, the target of RGCs in the brain of lower vertebrates, stimulated RGC dendritic arborization (41). These results underline the importance of local and target-derived BDNF in the regulation of RGC dendritic morphology during development. Afferent activity is another important factor in the regulation of dendritic growth and patterning of RGCs. During development, RGCs extend dendritic processes throughout the inner plexiform layer before becoming committed to any specific sublamina. In the mature retina, the dendrites of OFF RGCs arborize in sublamina a, where they receive input from OFF bipolar cells, whereas the ON RGC dendrites are confined to sublamina b, where they contact ON bipolar cells (42,43). This dendritic remodeling coincides with the developmental period when bipolar cells establish synaptic contacts with RGCs (44). Bodnarenko and Chalupa (45) addressed the question of whether bipolar cell input played a significant role in the distinct stratification pattern of ON or OFF RGC dendrites. Pharmacologic inhibition of glutamate release from ON bipolar cells during the period of normal stratification prevented segregation of RGC dendritic arbors within the inner plexiform layer. Moreover, blockade of visual stimulation during dark rearing delayed dendritic arbor segregation of ON and OFF RGCs after eye opening (46). These data provide compelling examples of the importance of afferent activity in RGC dendritic patterning during development. After maturation, dendrites become more stable structures and the morphology of the dendritic tree defines how signals propagate from the synapse toward the cell body. The dendritic arbors of adult neurons, however, can undergo substantial structural remodeling and plasticity. In the following sections, we provide examples of phys-iologic and pathologic alterations of dendritic arbors in mature neurons. PATHOLOGIC ALTERATIONS OF DENDRITIC MORPHOLOGY During normal development of the nervous system, there is selective elimination of dendrites and axons without loss of the neuron itself (47). This process aims to refine neuronal processes and to ensure precise connectivity. Dendritic and axonal retraction is also found in mature neurons in many neurologic diseases, including Alzheimer disease (48-51), Parkinson disease (52-54), Huntington disease (55,56), and glaucoma (57-60), but these morpho-logic alterations are often accompanied by substantial neu-ronal death. A key question is whether dendritic atrophy is a prerequisite or a consequence of neurodegeneration. Of interest, a study by Weber et al (60) showed that the earliest signs of glaucomatous damage involve RGC dendrite abnormalities. They found a significant reduction in the size of RGC dendritic fields in primate glaucomatous eyes compared with normal eyes. Other studies have reported similar findings in feline (61) and rat (62) glaucoma models: increased intraocular pressure led to a reduction in dendritic field radius, total dendritic length and number of branches. Importantly, morphologic changes of RGC dendritic arbors were detected slightly before axon thinning or soma shrink-age, suggesting that dendritic abnormalities may precede degeneration of other ganglion cell compartments. More recently, a clear correlation between abnor-malities of parasol RGC dendrite morphology and function has been established in a primate glaucoma model (59). Although RGCs in glaucomatous eyes retain most of their intrinsic electrical properties, their spatial and temporal response to visual stimuli is significantly reduced. Of interest, dendritic damage by chronic intraocular pressure elevation in a feline glaucoma model was more pronounced in Y-type than in X-type RGCs (61). This finding sug-gests that distinct RGC subpopulations have differential 147 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Morquette and Di Polo resistance to glaucomatous damage, which may correlate with their intrinsic morphologic and functional properties. In summary, early changes in RGC dendritic structure have critical consequences on synaptic efficacy and may underlie functional deficits in glaucoma. AGING MAKES YOUR DENDRITES CHANGE Demographic studies have shown that age is the best correlate of blindness and visual impairment (63). The normal function of eye tissues decreases dramatically with age, leading to a higher incidence of ocular pathologic changes and blinding diseases. The main causes of age-related vision loss are cataract, glaucoma, age-related macular degeneration, and diabetic retinopathy (64). It has been proposed that variations in the normal ocular aging process shift the balance toward the initiation of pathologic vision loss and its progression. For example, age-related stress such as oxidative damage has been shown to alter aqueous humor dynamics in the eye (65), which may explain the predisposition of aging individuals to develop glaucoma. Even in the absence of disease, many older adults experience a variety of visual defects including decreased visual acuity, and reduced temporal and contrast sensitivity, motion perception, and color discrimination (66). A traditional view has been that functional decline during aging, whether it is visual, cognitive, or other, is caused by massive neuronal loss. Indeed, a progressive loss of RGCs occurs naturally with increasing age in humans (67,68) and experimental animals (69-72). Loss of rod and cone photoreceptors (73) as well as retinal pigment epithelial cells (74) has also been described in the aging human retina. It has been hypothesized that these changes account for most of the functional deficits of aging. This view is now being challenged by new data demonstrating that age-related neuronal changes, which may underlie functional deficits, are more subtle. Age-related neuronal changes often involve remodeling of dendritic arbors and branches, connectivity between cells, changes in gene expression, and other factors that regulate neuronal plasticity (75). For example, in the prefrontal cortex, one of the brain regions most vulnerable to the effects of aging, there is a substantial decrease in dendritic arborization and branching in a large number of neurons in aging rats (76,77) and humans (78,79). Age-related dendritic changes (abnormal arbors and spines) have also been described in the hippocampus (80) in addition to loss of functional synapses (81). Recently, morphologic analysis of the retina of normal, aging mice (> 1 year) revealed aberrant dendritic growth (82). Specifically, rod bipolar cells in aging retinas extended dendritic processes to the outer nuclear layer, well beyond their normal boundary in the outer plexiform layer. Of interest, rod bipolar cell dendritic remodeling occurred in the absence of significant loss of rod or bipolar cells. In normal aging human retinas, the dendritic fibers of rods, ON cone bipolar cells, and horizontal cells were also found to extend abnormally into the outer nuclear layer, beyond their normal stratification site in the outer plexiform layer (83). Collectively, these data demonstrate a high degree of plasticity in dendrites of aging neurons, suggesting that age-related functional impairments may arise from aberrant dendritic remodeling. DENDRITIC SPINES: MORPHOLOGICAL SIGNATURES OF SYNAPTIC TRANSMISSION Dendritic spines are small protrusions emerging from the dendrites of many types of neurons in the central nervous system. They are the primary postsynaptic site of excitatory glutamatergic inputs onto neurons and, as such, play a key role in connectivity. Spines are present in different populations of neurons in the brain, and their development has been particularly well characterized in cerebellar Purkinje cells and pyramidal cells of the neo-cortex and hippocampus (84). The dendrites of developing RGCs are decorated with many spines, but most of these are lost during maturation of the retina (85,86). In the adult retina, spine-like processes remain only in a subset of RGCs (87-89). Dendritic spines have variable size and shape, but typically consist of a bulbous head up to 1 um in diameter connected to the dendritic shaft by a narrow stalk that can range from 40 to >200 nm. Several shapes of dendritic spines have been described: 1) type 1, or stubby spines, are short swellings of the dendritic tree of <0.5 mm in length that lack a head; 2) type 2, or mushroom spines, have a short constricted neck and a large irregular head; 3) type 3, or thin spines, consist of a long thin neck ending in a small bulbous head (Fig. 4) (90,91). Interestingly, the size of a spine is closely related to the size of the excitatory synapse area itself and thus its synaptic strength (92). Moreover, the spine surface area, spine volume, and axonal button volume are closely correlated with the number of presynaptic vesicles within the synaptic area. As a conse-quence, the shape and size of a dendritic spine can provide information about the efficacy and strength of a synapse. Recent studies using powerful imaging techniques have demonstrated that dendritic spines are extremely dynamic structures both in vitro and in vivo (93). The availability of novel high-resolution imaging methods, such as multiphoton microscopy and total internal reflection fluorescence microscopy, allow spine morphology to be imaged in living neurons with great detail (94). Changes in spine morphology from one shape to another, retraction and extension or appearance and disappearance, can occur rapidly within a scale of seconds to minutes (95,96). 148 © 2008 Lippincott Williams & Wilkins Retinal Ganglion Cells J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Mushroom spine Stubby spine FIG. 4. Dendritic spines of RGCs. They are the primary postsynaptic site of excitatory glutamatergic in-puts onto neurons and play a key role in connectivity. Spines have been classified by their size and shape as mushroom spines, stubby spines, thin spines, and filopodia. Inset shows a high magnification cartoon of a synapse between a spine and an axon. SV, synaptic vesicles; PSD, postsynaptic density. The actin-based cytoskeleton of dendritic spines (97) enables these speedy changes in shape and length. Using an isolated retina preparation, Wong et al (98) demonstrated that chick RGCs undergo extensive and rapid dendritic remodeling during development Specifically, individual RGC spine-like processes displayed rapid and diverse movements including extension and retraction within seconds (see movie at http://thalamus.wustl.edu/wonglab/images/nlipodia.avi). Of interest, younger RGCs showed a greater degree of dendritic process motility than older neurons. The functional role of dendritic spine dynamics is not entirely clear, but it has been proposed that it helps to establish synaptic connections by facilitating the initial contact between dendrites and axons (93). Although spine motility markedly decreases as the nervous system matures and dendrites become more stable (95), there is evidence of dendritic spine movement and plasticity in adult neurons of the somatosensory cortex (99) and visual cortex (100). Importantly, dendritic spine motility and morphologic changes have also been associated with pathologic conditions in the developing and mature nervous system (see below). DENDRITIC SPINE PATHOLOGY Abnormalities in dendritic spines have been corre-lated with a long list of medical conditions including mental retardation, malnutrition, hypoxia, ischemia, trau-matic brain injury, and neurodegenerative diseases (101- 103). Because spines are critical for synaptic function, it is likely that altered spine structure will have detrimental consequences on neuronal function. Fiala et al (102) provided a general classification of pathologic changes of dendritic spines based on 1) abnormalities of spine dis-tribution; and 2) abnormalities of spine ultrastructure. Pathologic changes of spine distribution reflect changes in a large number of spines along the parent dendrite such as spine loss, reduction or increase in spine density, or 149 J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 Morquette and Di Polo distorted shape. Pathologic changes of spine structure include aberrant changes at the level of a single spine such as electron-dense spines, alterations of spine organelles or postsynaptic density, and spine hypertrophy. Psychiatric disorders such as mental retardation, schizophrenia, epilepsy, and bipolar disorders fall in the category of diseases characterized by abnormal dendritic spine density and shape. For example, analysis of cortical neurons in Down syndrome revealed a marked reduction in the density of spines as well as distorted spine shapes (104- 106). Of interest, loss of spines concomitant with an abnormal increase in the remaining protrusions is apparent in neurons from individuals with mental retardation of unknown origin (107,108). Similarly, aberrantly long and tortuous spines are found in other forms of mental retardation including fragile-X syndrome (109), Patau syndrome (110) and fetal alcohol syndrome (111). Den-dritic spine abnormalities have also been reported in the hippocampus of humans and experimental animals with epilepsy (112). The effect of an acute epileptic insult on dendritic spine structure has been investigated by McKinney et al (90) using mouse hippocampal slices. Epileptiform activity, induced by extracellular electrical stimulation and blockade of GABAA receptors, led to substantial and rapid decreases in spine length of CA1 hippocampal neurons. Loss of dendritic spines is also a feature of pro-gressive neurodegenerative diseases. In Alzheimer disease, dendritic spines are lost from hippocampal pyramidal neurons, dentate granule neurons, and neocortical pyrami-dal neurons (113-117). Similarly, in Parkinson disease there is a reduction in spine density on neurons of the basal ganglia (118) and in severe Huntington disease there is a decreased number of spines in striatal neurons (119). Although subpopulations of RGCs contain spine-like processes in the mature retina (87), to our knowledge there have been no studies on dendritic spine changes during RGC death in glaucoma or other optic neuropathies. In conclusion, a reduction of dendritic spine density in these diseases is likely to go hand in hand with a reduction in excitatory input to neurons, exacerbating the functional deficits that accompany neurodegeneration. DENDRITIC CHANGES IN RGC POSTSYNAPTIC TARGETS IN THE BRAIN The previous sections dealt with changes in dendritic arbors and spine morphology with a focus on what is known or unknown about these changes in RGCs. A dif-ferent question is: what might be the significance of dendritic changes in postsynaptic neurons, specifically RGC targets in the brain? The vast majority of RGCs establish terminal synapses in the lateral geniculate nucleus (LGN), the major visual center that relays information to the primary visual cortex. In the LGN, parallel visual pathways are segregated into anatomical channels known as magnocellular, parvocellular, and koniocellular (120). LGN relay neurons project their axons to eye-specific columns in the primary visual cortex for further processing of visual information. There is now evidence that target neurons in these visual centers undergo atrophy or death in experimental and clinical glaucoma. Atrophy and shrinkage of LGN neurons is apparent in primate glaucoma models (121,122), and there is a clear correlation between transneuronal de-generation, level of intraocular pressure increase, and severity of RGC loss. Furthermore, evidence of neuronal death is seen at early, moderate, and advanced stages of glaucoma and involves neurons in the magnocellular, parvocellular, and koniocellular layers (123). A clinico-pathologic case of human glaucoma demonstrated de-generative changes in the lateral geniculate nucleus and visual cortex (124). In addition to cell body shrinkage, substantial reduction in dendritic field and complexity has been shown in LGN neurons in experimental primate glaucoma (125). The significant disruption of the normal LGN neuron architecture has been attributed to reduced afferent input from RGCs. In summary, LGN neuronal shrinkage and dendritic abnormalities indicate that glau-comatous damage is not confined to the RGCs and optic nerve but that it also involves other visual centers in the brain. These observations have important implications for the treatment and management of this disease. SUMMARY AND FUTURE DIRECTIONS: A HOLISTIC APPROACH TO NEUROPROTECTION A hallmark of neurodegenerative diseases is the death or atrophy of neurons with consequent loss of function. It has become clear, however, that individual cellular com-partments are affected differently during the process of neuronal degeneration (126). A long-standing and contro-versial question in the field has been: is the axon or the cell body affected first in disease? Glaucoma and other optic neuropathies have been traditionally viewed as diseases of the optic nerve in which RGC axons sustain the initial insult followed by de-generation of RGC soma (34). Recent experimental evi-dence supports this view. For example, morphologic analysis of RGCs in a rat glaucoma model showed higher loss of axons than cell bodies at different times after an intraocular pressure increase, suggesting that axons are affected first (23). Moreover, damage in the optic nerve was detected much earlier ( 1 month) than in RGC bodies in DBA/2J mice, a model of inherited glaucoma (127). 150 © 2008 Lippincott Williams & Wilkins Retinal Ganglion Cells J Neuro-Ophthalmol, Vol. 28, No. 2, 2008 A caveat from this type of analysis is that morphologic correlates are obtained from relatively large populations of RGCs, in which neurons can be at different stages of the neurodegenerative process, and data are captured at a moment frozen in time. Future studies are required to establish the precise time course of RGC axon versus soma loss in glaucoma. With the advent of novel imaging techniques, live monitoring of single RGCs may provide information on continuous structural changes in each cel-lular compartment during the degenerative process. In this review, we have focused on how dendrites, dendritic spines, and synaptic terminals are involved in the degenerative process and the likely functional consequen-ces of these structural changes. There is evidence that atrophy of RGC dendrites precedes cell body shrinkage and axonal breakdown in glaucoma, suggesting that dendritic abnormalities may be an early and prominent feature of vision loss in this disease (59,62,128). There is evidence of early dendritic and synaptic loss in other neurodegenerative diseases (102,126). Thus, dendritic protection and the preservation of synapses appear to be fundamental in preventing loss of neuronal function. Neuroprotection targeted to specific cell compart-ments has provided insight into the molecular mechanisms involved in neurodegeneration. However, experimental evidence indicates that compartmentalized neuroprotection fails to globally rescue neurons and restore function. 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