MCT2 overexpression rescues metabolic vulnerability and protects retinal ganglion cells in two models of glaucoma.
Glaucoma; Metabolism; Monocarboxylate transporter; Ocular hypertension; Retinal ganglion cell
Improving cellular access to energy substrates is one strategy to overcome observed declines in energy production and utilization in the aged and pathologic central nervous system. Monocarboxylate transporters (MCTs), the movers of lactate, pyruvate, and ketone bodies into or out of a cell, are significantly decreased in the DBA/2 J mouse model of glaucoma. In order to confirm MCT decreases are disease-associated, we decreased MCT2 in the retinas of MCT2(fl/+) mice using an injection of AAV2-cre, observing significant decline in ATP production and visual evoked potential. Restoring MCT2 levels in retinal ganglion cells (RGCs) via intraocular injection of AAV2-GFP-MCT2 in two models of glaucoma, the DBA/2 J (D2), and a magnetic bead model of ocular hypertension (OHT), preserved RGCs and their function. Viral-mediated overexpression of MCT2 increased RGC density and axon number, reduced energy imbalance, and increased mitochondrial function as measured by cytochrome c oxidase and succinate dehydrogenase activity in both models of glaucoma. Ocular hypertensive mice injected with AAV2:MCT2 had significantly greater P1 amplitude as measured by pattern electroretinogram than mice with OHT alone. These findings indicate overexpression of MCT2 improves energy homeostasis in the glaucomatous visual system, suggesting that expanding energy input options for cells is a viable option to combat neurodegeneration.
Harun-Or-Rashid Mohammad; Pappenhagen Nathaniel; Zubricky Ryan; Coughlin Lucy; Jassim Assraa Hassan; Inman Denise M
Neurobiology of disease
2020
2020-05-15
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1016/j.nbd.2020.104944" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2020.104944</a>
Upregulation of monocarboxylate transporter 2 protects retinal ganglion cells in glaucoma
Pappenhagen Nate; Harun-Or-Rashid Mohammad; Jaboori Assraa Jassim; Inman Denise M
Investigative Ophthalmology & Visual Science
2019
2019-07
Journal Article
<a href="https://iovs.arvojournals.org/article.aspx?articleid=2741271" target="_blank" rel="noreferrer noopener">https://iovs.arvojournals.org/article.aspx?articleid=2741271</a>
Glaucoma-associated E50K-optineurin mutation impairs mitochondrial-derived vesicle trafficking
Powers James; Trautman-Buckley Kayla; Sun Emily; Chen Charlaine; Inman Denise M; Tseng Henry
Investigative Ophthalmology & Visual Science
2019
2019-07
Journal Article
<a href="https://iovs.arvojournals.org/article.aspx?articleid=2741309">https://iovs.arvojournals.org/article.aspx?articleid=2741309</a>
Pre-degenerative Accumulation of Superoxide and Hydroxide in a Chronic Mouse Model of Glaucoma
Jassim Assraa Hassan; Inman Denise M
Investigative Ophthalmology & Visual Science
2019
2019-07
Journal Article
<a href="https://iovs.arvojournals.org/article.aspx?articleid=2741311" target="_blank" rel="noreferrer noopener">https://iovs.arvojournals.org/article.aspx?articleid=2741311</a>
Higher Reliance on Glycolysis Limits Glycolytic Responsiveness in Degenerating Glaucomatous Optic Nerve.
Glaucoma; Mitochondria; DBA/2J; Fluorocitrate; Optic nerve; Seahorse analyzer
Metabolic dysfunction accompanies neurodegenerative disease and aging. An important step for therapeutic development is a more sophisticated understanding of the source of metabolic dysfunction, as well as to distinguish disease-associated changes from aging effects. We examined mitochondrial function in ex vivo aging and glaucomatous optic nerve using a novel approach, the Seahorse Analyzer. Optic nerves (ON) from the DBA/2J mouse model of glaucoma and the DBA/2-Gpnmb(+) control strain were isolated, and oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), the discharge of protons from lactate release or byproducts of substrate oxidation, were measured. The glial-specific aconitase inhibitor fluorocitrate was used to limit the contribution of glial mitochondria to OCR and ECAR. We observed significant decreases in maximal respiration, ATP production, and spare capacity with aging. In the presence of fluorocitrate, OCR was higher, with more ATP produced, in glaucoma compared to aged ON. However, glaucoma ON showed lower maximal respiration. In the presence of fluorocitrate and challenged with ATPase inhibition, glaucoma ON was incapable of further upregulation of glycolysis to compensate for the loss of oxidative phosphorylation. Inclusion of 2-deoxyglucose as a substrate during ATPase inhibition indicated a significantly higher proportion of ECAR was derived from TCA cycle substrate oxidation than glycolysis in glaucoma ON. These data indicate that glaucoma axons have limited ability to respond to increased energy demand given their lower maximal respiration and inability to upregulate glycolysis when challenged. The higher ATP output from axonal mitochondria in glaucoma optic nerve compensates for this lack of resiliency but is ultimately inadequate for continued function.
Jassim Assraa Hassan; Coughlin Lucy; Harun-Or-Rashid Mohammad; Kang Patrick T; Chen Yeong-Renn; Inman Denise M
Molecular neurobiology
2019
2019-04
<a href="http://doi.org/10.1007/s12035-019-1576-4" target="_blank" rel="noreferrer noopener">10.1007/s12035-019-1576-4</a>
Early Cytoskeletal Protein Modifications Precede Overt Structural Degeneration in the DBA/2J Mouse Model of Glaucoma.
glaucoma; phosphorylation; amyloid-beta; axonal transport; cytoskeleton; neurofilament; spectrin; tau
Axonal transport deficits precede structural loss in glaucoma and other neurodegenerations. Impairments in structural support, including modified cytoskeletal proteins, and microtubule-destabilizing elements, could be initiating factors in glaucoma pathogenesis. We investigated the time course of changes in protein levels and post-translational modifications in the DBA/2J mouse model of glaucoma. Using anterograde tract tracing of the retinal projection, we assessed major cytoskeletal and transported elements as a function of transport integrity in different stages of pathological progression. Using capillary-based electrophoresis, single- and multiplex immunosorbent assays, and immunofluorescence, we quantified hyperphosphorylated neurofilament-heavy chain, phosphorylated tau (ptau), calpain-mediated spectrin breakdown product (145/150 kDa), beta-tubulin, and amyloid-beta42 proteins based on age and transport outcome to the superior colliculus (SC; the main retinal target in mice). Phosphorylated neurofilament-heavy chain (pNF-H) was elevated within the optic nerve (ON) and SC of 8-10 month-old DBA/2J mice, but was not evident in the retina until 12-15 months, suggesting that cytoskeletal modifications first appear in the distal retinal projection. As expected, higher pNF-H levels in the SC and retina were correlated with axonal transport deficits. Elevations in hyperphosphorylated tau (ptau) occurred in ON and SC between 3 and 8 month of age while retinal ptau accumulations occurred at 12-15 months in DBA/2J mice. In vitro co-immunoprecipitation experiments suggested increased affinity of ptau for the retrograde motor complex protein dynactin. We observed a transport-related decrease of beta-tubulin in ON of 10-12 month-old DBA/2J mice, suggesting destabilized microtubule array. Elevations in calpain-mediated spectrin breakdown product were seen in ON and SC at the earliest age examined, well before axonal transport loss is evident. Finally, transport-independent elevations of amyloid-beta42, unlike pNF-H or ptau, occurred first in the retina of DBA/2J mice, and then progressed to SC. These data demonstrate distal-to-proximal progression of cytoskeletal modifications in the progression of glaucoma, with many of these changes occurring prior to complete loss of functional transport and axon degeneration. The earliest changes, such as elevated spectrin breakdown and amyloid-beta levels, may make retinal ganglion cells susceptible to future stressors. As such, targeting modification of the axonal cytoskeleton in glaucoma may provide unique opportunities to slow disease progression.
Wilson Gina N; Smith Matthew A; Inman Denise M; Dengler-Crish Christine M; Crish Samuel D
Frontiers in neuroscience
2016
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3389/fnins.2016.00494" target="_blank" rel="noreferrer noopener">10.3389/fnins.2016.00494</a>
Anterograde transport blockade precedes deficits in retrograde transport in the visual projection of the DBA/2J mouse model of glaucoma.
glaucoma; optic nerve; axonal transport; axonopathy; neurodegeneration; ocular; superior colliculi; vision disorders
Axonal transport deficits have been reported as an early pathology in several neurodegenerative disorders, including glaucoma. However, the progression and mechanisms of these deficits are poorly understood. Previous work suggests that anterograde transport is affected earlier and to a larger degree than retrograde transport, yet this has never been examined directly in vivo. Using combined anterograde and retrograde tract tracing methods, we examined the time-course of anterograde and retrograde transport deficits in the retinofugal projection in pre-glaucomatous (3 month-old) and glaucomatous (9-13 month old) DBA/2J mice. DBA/2J-Gpnmb (+) mice were used as a control strain and were shown to have similar retinal ganglion cell densities as C57BL/6J control mice-a strain commonly investigated in the field of vision research. Using cholera toxin-B injections into the eye and FluoroGold injections into the superior colliculus (SC), we were able to measure anterograde and retrograde transport in the primary visual projection. In DBA/2J, anterograde transport from the retina to SC was decreased by 69% in the 9-10 month-old age group, while retrograde transport was only reduced by 23% from levels seen in pre-glaucomatous mice. Despite this minor reduction, retrograde transport remained largely intact in these glaucomatous age groups until 13-months of age. These findings indicate that axonal transport deficits occur in semi-functional axons that are still connected to their brain targets. Structural persistence as determined by presence of estrogen-related receptor beta label in the superficial SC was maintained beyond time-points where reductions in retrograde transport occurred, also supporting that transport deficits may be due to physiological or functional abnormalities as opposed to overt structural loss.
Dengler-Crish Christine M; Smith Matthew A; Inman Denise M; Wilson Gina N; Young Jesse W; Crish Samuel D
Frontiers in neuroscience
2014
1905-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3389/fnins.2014.00290" target="_blank" rel="noreferrer noopener">10.3389/fnins.2014.00290</a>
Structural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration.
b-hydroxybutyrate; ketogenic diet; neural-glial interaction; optic nerve
Axon degeneration can arise from metabolic stress, potentially a result of mitochondrial dysfunction or lack of appropriate substrate input. In this study, we investigated whether the metabolic vulnerability observed during optic neuropathy in the DBA/2J (D2) model of glaucoma is due to dysfunctional mitochondria or impaired substrate delivery to axons, the latter based on our observation of significantly decreased glucose and monocarboxylate transporters in D2 optic nerve (ON), human ON, and mice subjected to acute glaucoma injury. We placed both sexes of D2 mice destined to develop glaucoma and mice of a control strain, the DBA/2J-Gpnmb(+), on a ketogenic diet to encourage mitochondrial function. Eight weeks of the diet generated mitochondria, improved energy availability by reversing monocarboxylate transporter decline, reduced glial hypertrophy, protected retinal ganglion cells and their axons from degeneration, and maintained physiological signaling to the brain. A robust antioxidant response also accompanied the response to the diet. These results suggest that energy compromise and subsequent axon degeneration in the D2 is due to low substrate availability secondary to transporter downregulation.SIGNIFICANCE STATEMENT We show axons in glaucomatous optic nerve are energy depleted and exhibit chronic metabolic stress. Underlying the metabolic stress are low levels of glucose and monocarboxylate transporters that compromise axon metabolism by limiting substrate availability. Axonal metabolic decline was reversed by upregulating monocarboxylate transporters as a result of placing the animals on a ketogenic diet. Optic nerve mitochondria responded capably to the oxidative phosphorylation necessitated by the diet and showed increased number. These findings indicate that the source of metabolic challenge can occur upstream of mitochondrial dysfunction. Importantly, the intervention was successful despite the animals being on the cusp of significant glaucoma progression.
Harun-Or-Rashid Mohammad; Pappenhagen Nate; Palmer Peter G; Smith Matthew A; Gevorgyan Victoria; Wilson Gina N; Crish Samuel D; Inman Denise M
The Journal of neuroscience : the official journal of the Society for Neuroscience
2018
2018-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1523/JNEUROSCI.3652-17.2018" target="_blank" rel="noreferrer noopener">10.1523/JNEUROSCI.3652-17.2018</a>
Reduced AMPK activation and increased HCAR activation drive anti-inflammatory response and neuroprotection in glaucoma.
AMP-activated protein kinase; AMP-Activated Protein Kinases/*metabolism; Animal; Animals; Biological; Calcium Binding Proteins – Metabolism; Calcium-Binding Proteins/metabolism; Cells – Drug Effects; Cells – Pathology; Diet; Disease Models; Eye Proteins/genetics; Female; G-Protein-Coupled – Metabolism; G-Protein-Coupled/*metabolism; Glaucoma; Glaucoma – Complications; Glaucoma – Pathology; Glaucoma/*complications/pathology; Impact of Events Scale; Inbred DBA; Inflammation – Etiology; Inflammation – Prevention and Control; Inflammation hydroxycarboxylic acid receptor; Inflammation/*etiology/*prevention & control; Ketogenic diet; Ketogenic/methods; Male; Membrane Glycoproteins; Membrane Glycoproteins/genetics; Mice; Microfilament Proteins – Metabolism; Microfilament Proteins/metabolism; Microglia/drug effects/pathology; Models; Mutation; Mutation/genetics; Neuroprotection/drug effects/*physiology; NLR Family; Optic Nerve – Pathology; Optic Nerve/pathology; Phosphotransferases – Metabolism; Proteins; Pyrin Domain-Containing 3 Protein/genetics/metabolism; Receptors; Retina – Drug Effects; Retina – Pathology; Retinal Ganglion Cells/drug effects/*pathology; Transgenic
BACKGROUND: Glaucoma is a chronic degenerative disease for which inflammation is considered to play a pivotal role in the pathogenesis and progression. In this study, we examined the impact of a ketogenic diet on the inflammation evident in glaucoma as a follow-up to a recent set of experiments in which we determined that a ketogenic diet protected retinal ganglion cell structure and function. METHODS: Both sexes of DBA/2J (D2) mice were placed on a ketogenic diet (keto) or standard rodent chow (untreated) for 8 weeks beginning at 9 months of age. DBA/2J-Gpnmb(+) (D2G) mice were also used as a non-pathological genetic control for the D2 mice. Retina and optic nerve (ON) tissues were micro-dissected and used for the analysis of microglia activation, expression of pro- and anti-inflammatory molecules, and lactate- or ketone-mediated anti-inflammatory signaling. Data were analyzed by immunohistochemistry, quantitative RT-PCR, ELISA, western blot, and capillary tube-based electrophoresis techniques. RESULTS: Microglia activation was observed in D2 retina and ON as documented by intense microglial-specific Iba1 immunolabeling of rounded-up and enlarged microglia. Ketogenic diet treatment reduced Iba1 expression and the activated microglial phenotype. We detected low energy-induced AMP-activated protein kinase (AMPK) phosphorylation in D2 retina and ON that triggered NF-kappaB p65 signaling through its nuclear translocation. NF-kappaB induced pro-inflammatory TNF-alpha,
Harun-Or-Rashid Mohammad; Inman Denise M
Journal of neuroinflammation
2018
2018-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12974-018-1346-7" target="_blank" rel="noreferrer noopener">10.1186/s12974-018-1346-7</a>
Erratum To: Early pro-inflammatory cytokine elevations in the DBA/2J mouse model of glaucoma.
Wilson Gina N; Inman Denise M; Dengler-Crish Christine M; Smith Matthew A; Crish Samuel D
Journal of neuroinflammation
2015
2015-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1186/s12974-015-0410-9" target="_blank" rel="noreferrer noopener">10.1186/s12974-015-0410-9</a>
Evidence of Hypoxic Glial Cells in a Model of Ocular Hypertension.
Purpose: Reoxygenation after hypoxia can increase reactive oxygen species and upregulate autophagy. We determined, for the first time, the impact of elevated IOP on hypoxia induction, superoxide accumulation, and autophagy in a bead model of glaucoma. Method: Ocular hypertension was achieved with magnetic bead injection into the anterior chamber. Before mice were killed, they were injected with pimonidazole for hypoxia detection and dihydroethidium (DHE) for superoxide detection. Total retinal ganglion cells (RGCs) and optic nerve (ON) axons were quantified, total glutathione (GSH) was measured, and retinal and ON protein and mRNA were analyzed for hypoxia (Hif-1alpha and Hif-2alpha), autophagy (LC3 and p62), and SOD2. Results: With IOP elevation (P \textless 0.0001), the retina showed significantly (P \textless 0.001) decreased GSH compared with control, and a significant decrease (P \textless 0.01) in RGC density compared with control. Pimonidazole-positive Muller glia, microglia, astrocytes, and RGCs were present in the retinas after 4 weeks of ocular hypertension but absent in both the control and after only 2 weeks of ocular hypertension. The ON showed significant axon degeneration (P \textless 0.0001). The mean intensity of DHE in the ganglion cell layer and ON significantly increased (P \textless 0.0001). The ratio of LC3-II to LC3-I revealed a significant increase (P \textless 0.05) in autophagic activity in hypertensive retinas compared with control. Conclusions: We report a novel observation of hypoxia and a significant decrease in GSH, likely contributing to superoxide accumulation, in the retinas of ocular hypertensive mice. The significant increase in the ratio of
Jassim Assraa H; Inman Denise M
Investigative ophthalmology & visual science
2019
2019-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1167/iovs.18-24977" target="_blank" rel="noreferrer noopener">10.1167/iovs.18-24977</a>
Mitochondrial morphology differences and mitophagy deficit in murine glaucomatous optic nerve.
*Disease Models; Adenosine Triphosphate/metabolism; Age Factors; Animal; Animals; autophagosome; Axons/pathology; Electron; Inbred DBA; Mice; Microscopy; mitochondria; Mitochondria/*pathology; Mitochondrial Degradation/*physiology; mitophagy; Myelinated/pathology; Nerve Fibers; Optic Nerve/*pathology
PURPOSE: Decreased ATP correlates with intraocular pressure exposure in the optic nerves of mice with glaucoma. To understand what underlies this energy deficit, we examined mitochondria in the myelinated optic nerve axons of the DBA/2J mouse, a model of glaucoma secondary to iris pigment disease, and the DBA/2(wt-gpnmb) control strain. METHODS: Mitochondrial length, width, surface area, and health status were measured in 30 electron microscopic fields within the myelinated portion of optic nerves from DBA/2J and DBA/2(wt-gpnmb) mice at 3, 6, and 10 months of age. Protein was isolated from optic nerve for analysis of PINK1, Parkin, LC3-I and -II, and lysosome-associated membrane protein 1 (LAMP1) by Western blot. RESULTS: The number of mitochondria in DBA/2J optic nerve was increased, and they had significantly smaller surface area. Mitochondria in DBA/2J were closer to the axolemma, more spatially isolated, and their cristae were more disrupted at every age group as compared to DBA/2(wt-gpnmb). Autophagosomes were significantly increased in DBA/2J optic nerve at all ages. Protein analysis showed higher LC3-II to LC3-I ratio in aged DBA/2J optic nerve than in DBA/2(wt-gpnmb). PINK1 and Parkin levels were not statistically different across age groups. LAMP1 was significantly decreased in the aged DBA/2J optic nerve. CONCLUSIONS: Decreased surface area, combined with reduced oxidative capacity in mitochondria from the aged DBA/2J axon, indicate that mitochondrial pathology may contribute to the energy deficit in glaucomatous optic nerve. Though autophagosomes were increased in DBA/2J optic nerve, the increased mitochondria and decreased LAMP1 suggest deteriorating mitochondria are not being efficiently recycled by mitophagy.
Coughlin Lucy; Morrison Richard S; Horner Philip J; Inman Denise M
Investigative ophthalmology & visual science
2015
2015-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1167/iovs.14-16126" target="_blank" rel="noreferrer noopener">10.1167/iovs.14-16126</a>
Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma.
*Astrocyte; *Axonopathy; *Glaucoma; *Gliosis; *Neurodegeneration; *Retinal ganglion cell; Animal; Animals; Astrocytes/*pathology; Axons/pathology; Disease Models; Glaucoma; Imaging; Inbred DBA; Mice; Nerve Degeneration/etiology/*pathology; Open-Angle/*pathology; Optic Nerve Diseases/etiology/*pathology; Optic Nerve/*pathology; Photomicrography; Retinal Ganglion Cells/*pathology; Three-Dimensional; Time Factors
Glaucoma challenges the survival of retinal ganglion cell axons in the optic nerve through processes dependent on both aging and ocular pressure. Relevant stressors likely include complex interplay between axons and astrocytes, both in the retina and optic nerve. In the DBA/2J mouse model of pigmentary glaucoma, early progression involves axonopathy characterized by loss of functional transport prior to outright degeneration. Here we describe novel features of early pathogenesis in the DBA/2J nerve. With age the cross-sectional area of the nerve increases; this is associated generally with diminished axon packing density and survival and increased glial coverage of the nerve. However, for nerves with the highest axon density, as the nerve expands mean cross-sectional axon area enlarges as well. This early expansion was marked by disorganized axoplasm and accumulation of hyperphosphorylated neurofilamants indicative of axonopathy. Axon expansion occurs without loss up to a critical threshold for size (about 0.45-0.50 mum(2)), above which additional expansion tightly correlates with frank loss of axons. As well, early axon expansion prior to degeneration is concurrent with decreased astrocyte ramification with redistribution of processes towards the nerve edge. As axons expand beyond the critical threshold for loss, glial area resumes an even distribution from the center to edge of the nerve. We also found that early axon expansion is accompanied by reduced numbers of mitochondria per unit area in the nerve. Finally, our data indicate that both IOP and nerve expansion are associated with axon enlargement and reduced axon density for aged nerves. Collectively, our data support the hypothesis that diminished bioenergetic resources in conjunction with early nerve and glial remodeling could be a primary inducer of progression of axon pathology in glaucoma.
Cooper Melissa L; Crish Samuel D; Inman Denise M; Horner Philip J; Calkins David J
Experimental eye research
2016
2016-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.exer.2015.11.016" target="_blank" rel="noreferrer noopener">10.1016/j.exer.2015.11.016</a>
Changes in ganglioside GM1 expression in glaucomic retina.
Pappenhagen Nate; Inman Denise M
Journal of neuroscience research
2018
2018-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/jnr.24273" target="_blank" rel="noreferrer noopener">10.1002/jnr.24273</a>
Persistence of intact retinal ganglion cell terminals after axonal transport loss in the DBA/2J mouse model of glaucoma.
*Axonal Transport/physiology; *bouton; *mitochondria; *neurodegeneration; *retinal; *RRID:IMSRJAX:000671; *RRID:IMSRJAX:007048; *RRID:SCR002716; *RRID:SCR002865; *superior colliculus; *synapse; Animal; Animals; Disease Models; Electron; Glaucoma/metabolism/*pathology; Imaging; Inbred DBA; Mice; Microscopy; Mitochondria/pathology; Neuroanatomical Tract-Tracing Techniques; Regression Analysis; Retinal Ganglion Cells/metabolism/*pathology; Scanning; Superior Colliculi/metabolism/*pathology; Synapses/metabolism/*pathology; Three-Dimensional; Visual Pathways/metabolism/pathology
Axonal transport defects are an early pathology occurring within the retinofugal projection of the DBA/2J mouse model of glaucoma. Retinal ganglion cell (RGC) axons and terminals are detectable after transport is affected, yet little is known about the condition of these structures. We examined the ultrastructure of the glaucomatous superior colliculus (SC) with three-dimensional serial block-face scanning electron microscopy to determine the distribution and morphology of retinal terminals in aged mice exhibiting varying levels of axonal transport integrity. After initial axonal transport failure, retinal terminal densities did not vary compared with either transport-intact or control tissue. Although retinal terminals lacked overt signs of neurodegeneration, transport-intact areas of glaucomatous SC exhibited larger retinal terminals and associated mitochondria. This likely indicates increased oxidative capacity and may be a compensatory response to the stressors that this projection is experiencing. Areas devoid of transported tracer label showed reduced mitochondrial volumes as well as decreased active zone number and surface area, suggesting that oxidative capacity and synapse strength are reduced as disease progresses but before degeneration of the synapse. Mitochondrial volume was a strong predictor of bouton size independent of pathology. These findings indicate that RGC axons retain connectivity after losing function early in the disease process, creating an important therapeutic opportunity for protection or restoration of vision in glaucoma. J. Comp. Neurol. 524:3503-3517, 2016. (c) 2016 Wiley Periodicals, Inc.
Smith Matthew A; Xia Christina Z; Dengler-Crish Christine M; Fening Kelly M; Inman Denise M; Schofield Brett R; Crish Samuel D
The Journal of comparative neurology
2016
2016-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/cne.24012" target="_blank" rel="noreferrer noopener">10.1002/cne.24012</a>