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D. M. Inman, P. J. Horner; Neurotrophin Receptor Expression in Retinal and Optic Nerve Microglia Changes With Glaucoma and Age in the DBA/2J Mouse Model. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3703.
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Microglia have been shown to express BDNF in various CNS injury contexts, including ocular hypertension. BDNF has also been shown to increase microglia cell number and mitochondrial output in vitro, suggesting a potential autocrine regulation of microglia through this neurotrophin and its receptor. In addition, truncated TrkB receptor expression in glial cells after CNS injury can deplete extracellular levels of BDNF, possibly affecting the health and survival of neurons such as retinal ganglion cells (RGCs). Microglia number and reactivity increase with glaucoma progression in the DBA/2J mouse model of glaucoma; therefore, we explored whether BDNF and its receptor TrkB contributes to microglial regulation in the retina and optic nerve.
Retina and optic nerve mRNA, protein and tissue sections from 6 week to 15-month-old DBA/2J mice and age-matched C57Bl/6 control mice were analyzed by qRT-PCR, Western blotting and immunohistochemistry.
Microglia immunolabeled with phosphorylated TrkB (pTrkB) were found in the retina and optic nerves of DBA/2J and C57Bl/6 mice up through 3 months of age. Microglia in C57Bl/6 optic nerve beyond 6 months of age did not immunolabel with pTrkB. Microglial pTrkB immunolabel declined and remained stable in DBA/2J optic nerve from 6 to 10 months. Significant pTrkB immunolabel upregulation was observed beyond 10 months, both within and exclusive of microglia, and it correlated with the level of optic nerve degeneration in the DBA/2J optic nerve. Until 6 months of age, both mouse strains demonstrated similar levels of BDNF, TrkB and truncated TrkB mRNA and protein. At 10 months in optic nerve, DBA/2J mice underwent a significant upregulation of BDNF mRNA concomitant with a significant downregulation of truncated TrkB mRNA. In retina, BDNF mRNA levels decreased significantly between 12 and 15 months, but only in DBA/2J. Truncated TrkB mRNA underwent gradual decline in DBA/2J retina between 9 and 15 months of age.
The differential expression and incidence of BDNF, TrkB and phosphorylated TrkB in microglia of the DBA/2J and C57Bl/6 mouse retina and optic nerve suggests there are glaucoma-specific alterations in how these neurotrophin partners are regulated that likely has implications for disease progression.
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