July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
EXCITOTOXIC PATHOLOGY: DESCRIPTION OF A MODEL IN THE VISUAL SYSTEM OF MICE
Author Affiliations & Notes
  • James Bender
    Wicking Dementia Research and Education Centre, Hobart, Tasmania, Australia
  • Alexander Cronk
    Wicking Dementia Research and Education Centre, Hobart, Tasmania, Australia
  • Nuri Guven
    School of Pharmacy, University of Tasmania, Hobart, Tasmania, Australia
    Santhera Pharmaceuticals, Switzerland
  • Rachel Atkinson
    Wicking Dementia Research and Education Centre, Hobart, Tasmania, Australia
  • Jacqueline Leung
    Wicking Dementia Research and Education Centre, Hobart, Tasmania, Australia
  • James Vickers
    Wicking Dementia Research and Education Centre, Hobart, Tasmania, Australia
  • Anna King
    Wicking Dementia Research and Education Centre, Hobart, Tasmania, Australia
  • Footnotes
    Commercial Relationships   James Bender, None; Alexander Cronk, None; Nuri Guven, None; Rachel Atkinson, None; Jacqueline Leung, None; James Vickers, None; Anna King, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 4904. doi:
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      James Bender, Alexander Cronk, Nuri Guven, Rachel Atkinson, Jacqueline Leung, James Vickers, Anna King; EXCITOTOXIC PATHOLOGY: DESCRIPTION OF A MODEL IN THE VISUAL SYSTEM OF MICE. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4904.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Axon degeneration is a key pathological process in neurodegenerative diseases and may result in neuronal disconnection or death. Excitotoxicity is a pathological process known to occur in a variety of diseases and is known to be capable of inducing axonal degeneration, however, the mechanisms are poorly understood. Cell culture studies have provided insight into our understanding of excitotoxicity and this can be further developed when studied in an in vivo context. The visual system presents as an ideal model to study axon degeneration because of its accessibility as a CNS structure and its well-defined anatomy. This study aimed to characterize an in vivo model of CNS excitotoxicity in the visual system of mice.

Methods : Intravitreal administration of either the excitotoxin kainic acid (KA, n=41), or a vehicle control (PBS, n=13) was performed on adult C57BL/6J mice. Optomotor analysis was performed on all mice as a measure of visual acuity at 1 day before and 1 and 7 days after surgery. Retinal flat-mounts were immunolabelled for cytoskeletal and glial markers. Transmission electron microscopy (TEM) was performed on optic nerve tissue to observe alterations to the morphology, myelin, and cytoskeletal profiles of the RGC axons.

Results : Optomotor analysis revealed that animals treated with 1mM KA demonstrated a loss of visual acuity 1 day after surgery, but had improved by 7 days. In contrast, mice treated with >1mM KA exhibited an absence of response at any point after surgery (p<0.001), while the performance of animals given <1mM KA or PBS were not significantly affected (p=0.343). Retinal flat-mounts revealed that there was a significantly (p<0.001) increased immunoreactivity of the astrocyte marker GFAP following KA exposure, indicating an astroglial response to the excitotoxin. Additionally, analysis of RGC axons suggested prominent changes to neurofilament and tubulin profile of RGCs. TEM revealed distinct alterations to the structure and number of RGC axons visible in the optic nerve, as well as alterations to the cytoskeletal and organelle profile of these axons.

Conclusions : These data increase our understanding of excitotoxic pathology and validate the use of the visual system as an in vivo model of excitotoxicity. We are presently using this model to assess therapeutic intervention and study the mechanisms of axon degeneration.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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