Retinal ganglion cells adapt to ionic stress in experimental glaucoma

Boal, Andrew M.; McGrady, Nolan R; Holden, Joseph M.; Risner, Michael L.; Calkins, David J.

doi:10.3389/fnins.2023.1142668

Cited by 4 publications

(2 citation statements)

References 68 publications

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“…This gene encodes the sodium/potassium-transporting ATPase subunit beta family b enzyme, which is essential in maintaining the electrochemical gradient across the cell membrane. Although ATP1B3 has not been directly linked to glaucoma, dysregulation of ion channel activity is known to disrupt ion balance within the retinal ganglion cells (Boal et al, 2023; Chen et al, 2013), leading to oxidative stress and apoptosis, both present in glaucomatous eyes (Ma et al, 2022). The decreased atp1b3b expression observed in aged killifish ganglion cells might thus indicate loss of cellular homeostasis and dysregulation of ion channel activity in retinal ganglion cells.…”

Section: Resultsmentioning

confidence: 99%

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Bergmans,

Noel,

Masin

et al. 2024

Preprint

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Age-related vision loss caused by neurodegenerative pathologies in the retina is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks. Bulk and single-cell RNA-sequencing (scRNA-seq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterised, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNA-seq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasises the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies.HighlightsThe aged killifish retina displays several ageing hallmarks, such as oxidative stress, gliosis, and inflammageing, at the transcriptome level.Risk genes for neurodegenerative disorders show dysregulation in the old killifish retina.All vertebrate retinal cell types are present in the killifish retina.Transcriptional dysregulation in the aged killifish retina is observed across cell types.Cell type-specific transcriptomic changes across age highlight increased stress response.

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Section: Resultsmentioning

confidence: 99%

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Bergmans,

Noel,

Masin

et al. 2024

Preprint

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“…Indeed, ONC in one eye can cause changes to the contralateral eye, and in one case RGCs in an uninjured eye showed dysfunction of intrinsic electrical properties (McGrady et al, 2022). Reduced intrinsic excitability has also been reported in other models of neuronal injury (Stys et al, 1992a;Stys et al, 1992b;Waxman et al, 1992;Boal et al, 2023). To examine the intrinsic properties of AlphaONS RGCs, we performed whole-cell patch-clamp recording in current clamp mode.…”

Section: Intrinsic Excitability Of Alphaons Rgcs Is Reduced Following...mentioning

confidence: 99%

Optic nerve injury impairs intrinsic mechanisms underlying electrical activity in a resilient retinal ganglion cell

Zapadka,

Tran,

Demb

2024

Preprint

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Retinal ganglion cells (RGCs) are the sole output neurons of the retina and convey visual information to the brain via their axons in the optic nerve. Following an injury to the optic nerve, RGCs axons degenerate and many cells die. For example, a surgical model of compressive axon injury, the optic nerve crush (ONC), kills ∼80% of RGCs after two weeks. Surviving cells are biased towards certain ‘resilient’ types, including several types that originally produced sustained firing to light stimulation. RGC survival may depend on activity level, and there is a limited understanding of how or why activity changes following optic nerve injury. Here we quantified the electrophysiological properties of a highly resilient RGC type, the sustained ON-Alpha RGC, seven days post-ONC with extracellular and whole-cell patch clamp recording. Both light- and current-driven firing were reduced after ONC, but synaptic inputs were largely intact. Resting membrane potential and input resistance were relatively unchanged, while voltage-gated currents were impaired, including a reduction in voltage-gated sodium channel density in the axon initial segment and function. Hyperpolarization or chelation of intracellular calcium partially rescued firing rates. These data suggest that an injured resilient RGC reduces its activity by a combination of reduced voltage-gated channel expression and function and downregulation of intrinsic excitability via a Ca2+-dependent mechanism without substantial changes in synaptic input. Reduced excitability may be due to degradation of the axon but could also be energetically beneficial for injured RGCs, preserving cellular energy for survival and regeneration.Graphical AbstractSchematic view of the effects of axon injury (optic nerve crush) on the physiology of an sustained ON-Alpha (AlphaONS) retinal ganglion cell. These cells are highly resilient to axon injury and survive for several weeks while other retinal ganglion cell types perish. At one week after injury, the AlphaONS RGC has diminished spontaneous and light-evoked action potential firing. Reduced firing depends not on changes in synaptic inputs but rather on reductions in intrinsic excitability. Reduced excitability is explained by a Ca2+-dependent mechanism and by a reduction in sodium channel density and function.Key Points Summary1)Retinal ganglion cell (RGC) types show diverse rates of survival after axon injury.2)A resilient RGC type maintains its synaptic inputs one week post-injury.3)The resilient RGC type shows diminished firing and reduced expression of axon initial segment (AIS) genes following injury4)Activity deficits arise from intrinsic dysfunction (Na+channels, intracellular Ca2+), not from loss of excitation or enhanced inhibition.

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Erigeron breviscapus: A Promising Medication for Protecting the Optic Nerve in Glaucoma

Cheng,

Chen,

Zhu

et al. 2024

Planta Med

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Glaucoma is a common eye condition characterized by the loss of retinal ganglion cells and their axons, optic nerve damage, and visual field defects, which seriously affect a patientʼs quality of life. The pathogenesis of glaucoma is still unclear at present. It presents as damage to retinal ganglion cells, and the main treatment is primarily to reduce intraocular pressure by surgery or taking medication. However, even with well-controlled intraocular pressure, retinal ganglion cells still undergo degeneration, progressive apoptosis, and axonal loss. Therefore, protecting the optic nerve and inhibiting the apoptosis of retinal ganglion cells are the current hot topic for prevention and treatment of glaucoma. Recently, Erigeron breviscapus, originating from Yunnan province in China, has been shown to be a promising herb with neuroprotective effects to treat glaucoma. Therefore, the traditional usage, botanical characteristics, and phytochemical composition of E. breviscapus were explored through a literature review. Furthermore, we have summarized the pharmacological mechanisms of E. breviscapus and its active components in inhibiting the apoptosis of retinal ganglion cells. These research findings can not only provide guidance and recommendations for the protection of retinal ganglion cells but also further explore the potential of E. breviscapus in the treatment of glaucoma.

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Retinal ganglion cells adapt to ionic stress in experimental glaucoma

Cited by 4 publications

References 68 publications

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Optic nerve injury impairs intrinsic mechanisms underlying electrical activity in a resilient retinal ganglion cell

Erigeron breviscapus: A Promising Medication for Protecting the Optic Nerve in Glaucoma

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