Dataset Information

Blast Preconditioning Protects Retinal Ganglion Cells and Reveals Targets for Prevention of Neurodegeneration Following Blast-Mediated Traumatic Brian Injury.

ABSTRACT: Purpose:The purpose of this study was to examine the effect of multiple blast exposures and blast preconditioning on the structure and function of retinal ganglion cells (RGCs), to identify molecular pathways that contribute to RGC loss, and to evaluate the role of kynurenine-3-monooxygenase (KMO) inhibition on RGC structure and function. Methods:Mice were subjected to sham blast injury, one single blast injury, or three blast injuries separated by either 1 hour or 1 week, using a blast intensity of 20 PSI. To examine the effect of blast preconditioning, mice were subjected to sham blast injury, one single 20-PSI injury, or three blast injuries separated by 1 week (5 PSI, 5 PSI, 20 PSI and 5 PSI, 5 PSI, 5 PSI). RGC structure was analyzed by optical coherence tomography (OCT) and function was analyzed by the pattern electroretinogram (PERG). BRN3A-positive cells were quantified to determine RGC density. RNA-seq analysis was used to identify transcriptional changes between groups. Results:Analysis of mice with multiple blast exposures of 20 PSI revealed no significant differences compared to one 20-pounds per square inch (PSI) exposure using OCT, PERG, or BRN3A cell counts. Analysis of mice exposed to two preconditioning 5-PSI blasts prior to one 20-PSI blast showed preservation of RGC structure and function. RNA-seq analysis of the retina identified multiple transcriptomic changes between conditions. Pharmacologic inhibition of KMO preserved RGC responses compared to vehicle-treated mice. Conclusions:Preconditioning protects RGC from blast injury. Protective effects appear to involve changes in KMO activity, whose inhibition is also protective.

SUBMITTER: Harper MM

PROVIDER: S-EPMC6785841 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Blast Preconditioning Protects Retinal Ganglion Cells and Reveals Targets for Prevention of Neurodegeneration Following Blast-Mediated Traumatic Brian Injury.

Harper Matthew M MM Woll Addison W AW Evans Lucy P LP Delcau Michael M Akurathi Abhigna A Hedberg-Buenz Adam A Soukup Dana A DA Boehme Nickolas N Hefti Marco M MM Dutca Laura M LM Anderson Michael G MG Bassuk Alexander G AG

Investigative ophthalmology & visual science 20191001 13

<h4>Purpose</h4>The purpose of this study was to examine the effect of multiple blast exposures and blast preconditioning on the structure and function of retinal ganglion cells (RGCs), to identify molecular pathways that contribute to RGC loss, and to evaluate the role of kynurenine-3-monooxygenase (KMO) inhibition on RGC structure and function.<h4>Methods</h4>Mice were subjected to sham blast injury, one single blast injury, or three blast injuries separated by either 1 hour or 1 week, using a ...[more]

PMID: 31598627

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Project description:Microglia play important roles in shaping the developing CNS, and at early stages they have been proposed to regulate progenitor proliferation, differentiation, and neuronal survival. However, these studies reveal contradictory outcomes, highlighting the complexity of these cell-cell interactions. Here, we investigate microglia function during embryonic mouse retina development, where only microglia, progenitors, and neurons are present. In both sexes, we determine that microglia primarily interact with retinal neurons and find that depletion of microglia via conditional KO of the Csf1 receptor results in increased density of retinal ganglion cells (RGCs). Pharmacological inhibition of microglia also results in an increase in RGCs, with no effect on retinal progenitor proliferation, RGC genesis, or apoptosis. We show that microglia in the embryonic retina are enriched for phagocytic markers and observe engulfment of nonapoptotic Brn3-labeled RGCs. We investigate the molecular pathways that can mediate cell engulfment by microglia and find selective downregulation of complement pathway components with microglia inhibition, and further show that C1q protein marks a subset of RGCs in the embryonic retina. KO of complement receptor 3 (CR3; Itgam), which is only expressed by microglia, results in increased RGC density, similar to what we observed after depletion or inhibition of microglia. Thus, our data suggest that microglia regulate neuron elimination in the embryonic mouse retina by complement-mediated phagocytosis of non-apoptotic newborn RGCs.SIGNIFICANCE STATEMENT Microglia are emerging as active and important participants in regulating neuron number in development, during adult neurogenesis, and following stem cell therapies. However, their role in these contexts and the mechanisms involved are not fully defined. Using a well-characterized in vivo system, we provide evidence that microglia regulate neuronal elimination by complement-mediated engulfment of nonapoptotic neurons. This work provides a significant advancement of the field by defining in vivo molecular mechanisms for microglia-mediated cell elimination. Our data add to a growing body of evidence that microglia are essential for proper nervous system development. In addition, we elucidate microglia function in the developing retina, which may shed light on microglia involvement in the context of retinal injury and disease.

Dataset Information

Blast Preconditioning Protects Retinal Ganglion Cells and Reveals Targets for Prevention of Neurodegeneration Following Blast-Mediated Traumatic Brian Injury.

Publications

Blast Preconditioning Protects Retinal Ganglion Cells and Reveals Targets for Prevention of Neurodegeneration Following Blast-Mediated Traumatic Brian Injury.

Similar Datasets

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