Abstract
ABSTRACTMicroglia 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.
Highlights
To assess the kinetics of early microgliosis and microglia activation, they used a DBA/2J reporter substrain in which microglia and infiltrating monocytes express green fluorescent protein (GFP) under the control of the fractalkine receptor locus (Cx3cr1), and imaged young mice at 1 to 5 months of age by confocal scanning laser ophthalmoscopy (cSLO) to monitor early microglial changes
Live images collected at pre-pathological ages revealed dynamic patterns of retinal microglial activation and an unexpected diversity in the levels of microgliosis at the optic nerve head (ONH), which was attenuated by minocycline
CSLO live imaging allows the tracking of cellular changes in retinal microglia and infiltrating monocytes that are localized adjacent to retinal ganglion cells (RGCs) somata, dendrites and unmyelinated axons across the inner retinal surface and ONH (Bosco et al, 2011)
Summary
Received 14 October 2014; Accepted 26 February 2015 and developing targeted therapies Such an early diagnostic and prognostic strategy depends on the detection of cellular and/or molecular markers dynamically linked with the pathogenic process of neurodegeneration. Microglia are long-lived myeloid cells that stably inhabit the adult CNS within parenchymal and perivascular niches (Kettenmann et al, 2011; Lawson et al, 1990, 1992; Prinz et al, 2011) They constantly interact with surrounding neurons, blood-brain barrier cells and other glia (Davalos et al, 2005; Nimmerjahn et al, 2005; Ransohoff and Cardona, 2010; Ransohoff and Perry, 2009; Tremblay et al, 2010; Wake et al, 2009). Microglia, as ubiquitous, dynamic sensors of CNS damage and dyshomeostasis, are ideally suited to detect and indicate the progression of pathogenic processes
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