title: Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma.
abstract: Microglia serve key homeostatic roles, and respond to neuronal perturbation and decline with a high spatiotemporal resolution. The course of all chronic CNS pathologies is thus paralleled by local microgliosis and microglia activation, which begin at early stages of the disease. However, the possibility of using live monitoring of microglia during early disease progression to predict the severity of neurodegeneration has not been explored. Because the retina allows live tracking of fluorescent microglia in their intact niche, here we investigated their early changes in relation to later optic nerve neurodegeneration. To achieve this, we used the DBA/2J mouse model of inherited glaucoma, which develops progressive retinal ganglion cell degeneration of variable severity during aging, and represents a useful model to study pathogenic mechanisms of retinal ganglion cell decline that are similar to those in human glaucoma. We imaged CX3CR1(+/GFP) microglial cells in vivo at ages ranging from 1 to 5 months by confocal scanning laser ophthalmoscopy (cSLO) and quantified cell density and morphological activation. We detected early microgliosis at the optic nerve head (ONH), where axonopathy first manifests, and could track attenuation of this microgliosis induced by minocycline. We also observed heterogeneous and dynamic patterns of early microglia activation in the retina. When the same animals were aged and analyzed for the severity of optic nerve pathology at 10 months of age, we found a strong correlation with the levels of ONH microgliosis at 3 to 4 months. Our findings indicate that live imaging and monitoring the time course and levels of early retinal microgliosis and microglia activation in glaucoma could serve as indicators of future neurodegeneration severity.
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA alejandra.bosco@neuro.utah.edu.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Bosco
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Cesar O
authors.initials: CO
authors.lastname: Romero
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Breen
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Alexis A
authors.initials: AA
authors.lastname: Chagovetz
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Steele
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Vetter
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D004195:Disease Models, Animal; D005260:Female; D005901:Glaucoma / Q000473:pathology*; D005911:Gliosis / Q000473:pathology; D007834:Lasers; D008297:Male; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D017628:Microglia / Q000473:pathology*; D009410:Nerve Degeneration / Q000473:pathology*; D009887:Ophthalmoscopy; D009898:Optic Disk / Q000473:pathology; D019707:Receptors, Chemokine / Q000378:metabolism; D012160:Retina / Q000473:pathology
chemical_list: D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine
keywords: Confocal ophthalmoscopy; Cx3cr1GFP/+ DBA/2J; Live image analysis; Microglia activation; Microgliosis; Retinal ganglion cells