June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Microglia depletion increases susceptibility for glaucomatous neurodegeneration in ocular hypertensive mice
Author Affiliations & Notes
  • Cory Alexander Diemler
    The Jackson Laboratory, Bar Harbor, Maine, United States
    University of Maine System, Bangor, Maine, United States
  • Travis Cossette
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Sarah Heuer
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Melanie Maddocks Goodrich
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Michael MacLean
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Olivia Marola
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Amanda Hewes
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Gareth Howell
    The Jackson Laboratory, Bar Harbor, Maine, United States
  • Footnotes
    Commercial Relationships   Cory Diemler None; Travis Cossette None; Sarah Heuer None; Melanie Maddocks Goodrich None; Michael MacLean None; Olivia Marola None; Amanda Hewes None; Gareth Howell None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1595. doi:
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      Cory Alexander Diemler, Travis Cossette, Sarah Heuer, Melanie Maddocks Goodrich, Michael MacLean, Olivia Marola, Amanda Hewes, Gareth Howell; Microglia depletion increases susceptibility for glaucomatous neurodegeneration in ocular hypertensive mice. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1595.

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

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Abstract

Purpose : Microglia responses occur early in the pathogenesis of glaucoma and other neurodegenerative diseases. In recent years, changes in microglial states have been correlated with later glaucoma severity; however, their specific role(s) are not known. We hypothesize that the depletion of microglia with a dietary CSF1R inhibitor would alter glaucomatous optic nerve damage in an aged ocular hypertensive model.

Methods : Dietary PLX5622, a CSF1R inhibitor known to decrease populations of microglia in the retina, was introduced to 9.5mo-old DBA/2J mice (a widely used model relevant to ocular hypertension). Microglial depletion was confirmed with retinal tissue RNA-seq analysis (n=4 per diet per sex). Intraocular pressures (IOPs) were measured, and retinal ganglion cell (RGC) function was assessed by measuring pattern electroretinography (PERG) amplitudes and latency at 9, 10.5, and 12mo of age. (n=10 per diet per sex). At 12mo, optic nerves were evaluated for glaucomatous damage using p-phenylenediamine staining (n=12 per diet per sex). Retinas corresponding to the assessed optic nerves were isolated for confocal microscopy (n=6 per diet).

Results : Pilot studies showed that 75% of retinal microglia are depleted after 3wks exposure to PLX5622. Microglia depletion was further validated by RNA-seq analysis that showed significant downregulation of microglia-specific genes including Tmem119, and P2ry12. 10wks exposure to PLX5622 revealed no significant differences in PERG amplitude and latency, IOP, or RGC soma number between dietary groups. However, analysis of optic nerves showed a significant PLX5622 diet-associated increase in moderate-to-severe optic nerve damage (p= 0.0022).

Conclusions : Our results indicate that reducing the retinal microglial population from 9.5 to 12mo increased susceptibility for glaucomatous neurodegeneration in DBA/2J mice. This suggests a potential beneficial effect of microglia in glaucoma. Experiments are underway to determine whether this overall beneficial effect can be boosted by renewing the microglia pool just prior to IOP onset and optic nerve damage through short term exposure to PLX5622. Future studies will include targeting specific states of microglia through disruption of genes known to control activation including the triggering receptor expressed on myeloid cells (TREM) gene family.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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