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A. Bosco, M. R. Steele, D. M. Inman, P. J. Horner, M. L. Vetter; Potential Role of Retinal Microglia in RGC Synapse Removal in DBA/2J Mice. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2770.
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© ARVO (1962-2015); The Authors (2016-present)
Complement component C1q mediates synapse elimination, and is upregulated by RGCs in the DBA/2J (D2) mouse model of glaucoma in association with early synapse loss (Stevens et al., 2007). We sought to determine whether microglia execute the C1q-mediated stripping of RGC synapses in the D2 retina. We analyzed the distribution of activated microglia relative to dendrite and synapse loss in the early D2 retina, and evaluated the protective effect of minocycline, known to decrease retinal microglia activation (Bosco et al., 2008, IOVS 49:1437-46).
To monitor changes in microglia and various RGC compartments, D2 mice at 1, 3, 5, 8 and 12 months of age (n=15 each) were immunostained for Iba1 (microglia), C1q, PSD95 (post-synaptic density), MAP1 (dendrites), p-neurofilament, alpha-internexin (RGC axons), Brn3b (RGC nuclei) then imaged by confocal microscopy. To suppress microglial activation a separate cohort of D2 mice was treated chronically with minocycline (120mg/kg) or vehicle from 2 to 7.5 months of age (Bosco et al., 2008). At 5 months of age, minocycline and vehicle-treated mice (n=4 each), as well as age-matched control DBA/2J Gpnmb+ mice (D2Gpnmb+; n=4) underwent identical histology and analysis using the markers above.
In D2, but not in D2Gpnmb+ control mice, we observed clustering and activation of Iba1+ microglia by 3 mo in D2 inner retina, optic nerve head and lamina which expanded and persisted at later ages. In 5 month-old D2 mice, at the time of reported synapse loss (Stevens et al., 2007), activated Iba1+ microglia flanked C1q+ RGCs. There was reduced dendritic branching in regions with diminished postsynaptic areas within the inner plexiform layer, which was not evident in age-matched D2Gpnmb+ retinas. Minocycline-treated D2 mice still upregulated expression of C1q within RGCs, but showed preservation of RGC dendritic and post-synaptic compartments at 5 months of age as compared to vehicle-treated or untreated age-matched animals.
We conclude that D2 mice, but not their congenic D2Gpnmb+ control sub-strain, exhibit early microglia activation, and association with regions of synaptic and dendritic depletion. The apparent preservation of RGC synapses and dendrites in minocycline-treated D2 mice with reduced microglia activation suggests that microglia may contribute to RGC decline in this model of chronic glaucoma.
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