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A. Bosco, M. R. Steele, M. L. Vetter; Microglia Cell Activation and Clustering Herald the Onset of Glaucoma in DBA/2J Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5492.
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© ARVO (1962-2015); The Authors (2016-present)
Since human glaucoma involves microgliosis (Yuan & Neufeld, 2001), and deactivation of microglia is protective in the DBA/2J mouse model of glaucoma (ARVO 2007 48:3291), we sought to quantitatively determine the spatial-temporal pattern of retinal microglia activation in DBA mice in relation to optic nerve axon changes. We analyzed ages preceding glaucomatous neurodegeneration through ages when retinal ganglion cell (RGC) pathology and maximal ocular hypertension are detectable to assess a role for microgliosis in disease onset or progression.
To detect retinal microgliosis, we analyzed retinal microglia distribution and activation state by densitometry, cell morphometry and qPCR in 1, 3, 5 and 8mo old DBA (n=50), compared to age-matched C57/Bl6 (n=32) and GFP-CX3CR1 (n=12). Protein and mRNA expression of Iba1, a microglia-specific activation marker, was compared between central (ONH) and peripheral retina, as well as CD115, CD11b, F4/80, CD4 mRNAs (n=10 per age). DBA microgliosis was correlated with intraocular pressure (IOP; monitored monthly with TonoPen and TonoLab) and with RGC axon dystrophy, evidenced by cytoskeletal protein buildup (phospho-neurofilament, α-internexin).
Activated microglia, identified by Iba1 upregulation, morphology and localization, concentrate early in the DBA ONH, the putative site of pathogenesis. The number of activated microglia cells increases 60% in the ONH by 3mo. and in the peripheral retina by 8mo, in both cases persisting until 8mo. Iba1 upregulation is detectable in the central retina by 3mo. (1.7x mRNA↑, 1.3x protein↑, compared to 1mo.), and in the peripheral retina by 8mo. (1.9x protein↑, compared to 1mo.). CD115, F4/80 and CD45 also are upregulated in the ONH by 3mo. Enlarged, solid microglia with upregulated Iba1 confine to the proximity of dystrophic RGC axons from 3-8 mo. There is general correlation between the timing of IOP rise and microgliosis. ONH microgliosis is not detectable in control mice.
Early microgliosis in the ONH, the putative site of pathogenesis, and the later co-localization of activated microglia in sectors with pathologic RGC axons suggest that retinal microglia activation is coupled with axon impairment in DBA mice.
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