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Zizhu Tan, Yinjie Guo, Maleeka Shrestha, Meredith S Gregory-Ksander, Tatjana C Jakobs; Depletion of optic nerve microglia does not improve visual function in experimental glaucoma. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2383.
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Microglia become reactive in response to pathological stimuli, such as an increase in IOP. It has been reported that depending on the nature and the duration of the insult activated microglia in the brain can instruct neighboring astrocytes to assume a predominantly neuroprotective or a predominantly neurotoxic phenotype (Liddelow et al, 2017). We tested whether depletion of microglia with the CSF1R inhibitor PLX5622 has an effect on the visual function or ganglion cell loss during experimental glaucoma. We also compared the gene expression profile of isolated astrocytes from microglia-depleted and control nerves over a 4-weeks course of IOP elevation.
Two groups of C57BL/6 mice were placed on microglia depletion diet (n=32) or control diet (n=26) for 3 weeks. Magnetic microbeads were injected into the anterior chamber of the right eye. Visual function was measured by pattern ERG and observation of the optomotor reflex. Retinal ganglion cells and axons were counted. In addition, a cohort of mice received either depletion or control diet and microbead injection. At 7 days, 14 days, 21 days, and 28 days after injection the optic nerve heads were dissociated and individual astrocytes from were collected under microscopic control. The gene expression profile was assayed by quantitative PCR.
Treatment with PLX5622 led to complete depletion of microglia from the retina over the time course of the study. However, there was a small population of cells with microglial morphology that remained in the myelinated portion of the optic nerve even after 7 weeks total on the PLX5622 diet. IOP elevation led to a significant decrease of visual acuity (0.296 ± 0.072 versus 0.42 ±0.017 cycles/degree in the control group, p<0.001), whereas saline injection had no effect on the IOP or the visual acuity. Pattern ERG amplitude was decreased from 21.46 ± 4.9 uV at baseline to 14.33 ± 4.6 uV after microbead injection (p<0.001). However, there was no significant difference between the microglia depleted and the control groups. Genes associated with the putative neuroprotective astrocyte phenotype were up-regulated under control conditions. In astrocytes from microglia-depleted nerves this up-regulation was attenuated.
Our preliminary results suggest that microglia depletion does not appear to be a promising strategy to improve visual function in experimental glaucoma.
This is a 2021 ARVO Annual Meeting abstract.
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