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Stewart A Bloomfield, Sandeep Kumar, Abram Akopian; Neuroprotection of retinal ganglion cells suppresses microglia activation in a mouse model of glaucoma. Invest. Ophthalmol. Vis. Sci. 2020;61(7):641.
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© ARVO (1962-2015); The Authors (2016-present)
Changes in microglia activation occur under numerous neuropathological insults, including glaucoma. We showed recently that blockade of neuronal gap junctions (GJs) or ablation of their connexin36 (Cx36) subunits provides significant neuroprotection of retinal ganglion cells (RGCs) in animal models of glaucoma by eliminating bystander cell death. Here, we examined whether direct neuroprotection of RGCs by GJ disruption can also prevent the activation of microglia associated with glaucoma.
Experiments were performed on the microbead-occlusion mouse model of glaucoma in which IOP is elevated for at least 8 weeks. Comparisons were made between measures of microglia activation in microbead-injected eyes of control mice and those either pretreated with the GJ blocker MFA or Cx36-/- (knockout) mice, the latter two in which RGCs are protected against GJ-mediated bystander cell death associated with glaucoma (Akopian et al., 2017 JCI). Immunolabeling was performed using antibodies against Iba1, a general marker for microglia, and against MHCII, a marker for active microglia.
All microglia cells were Iba1+/MHCII- under control conditions and formed a regular mosaic with non-overlapping processes of neighboring cells. Beginning one week after microbead injection and elevated IOP, the number of Iba1+/MHCII- cells was increased slightly and showed hypertrophy in the form of enlarged somata and retracted thick processes. Between 4-8 weeks after injection there was a marked proliferation (17-82% increase) of Iba1+ microglia compared to control measures. Observation of activated microglia (MCHCII+) was first made at 4 weeks, comprising 17% of all microglia, which increased to 79% by 8 weeks post injection. In contrast, at 8 weeks we found no statistically significant change in microglia numbers, activation (MHCII labeling), or hypertrophy in microbead-injected eyes of MFA-treated or Cx36-/- mice in which RGC survivability reached >90% of control values.
Our results indicate that microglia activation coincides temporally with neuronal loss. However, direct neuroprotection of RGCs by eliminating GJ-mediated bystander cell death eliminated microglia activation. These data indicate a direct link between RGC loss and microglia activation and, moreover, show that protection of RGCs by disruption of neuronal GJs also suppresses the glial response even with continued IOP elevation.
This is a 2020 ARVO Annual Meeting abstract.
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