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Updated: Jul 15, 2026
Primary Microglia Isolation from Mixed Glial Cell Cultures of Neonatal Rat Brain Tissue
Published on: August 15, 2012
System xc- and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes
María Domercq1, María Victoria Sánchez-Gómez, Catherine Sherwin
1Departamento de Neurociencias, Universidad del País Vasco, Leioa, Vizcaya, Spain.
Abstract:
Elevated levels of extracellular glutamate cause excitotoxic oligodendrocyte cell death and contribute to progressive oligodendrocyte loss and demyelination in white matter disorders such as multiple sclerosis and periventricular leukomalacia. However, the mechanism by which glutamate homeostasis is altered in such conditions remains elusive. We show here that microglial cells, in their activated state, compromise glutamate homeostasis in cultured oligodendrocytes. Both activated and resting microglial cells release glutamate by the cystine-glutamate antiporter system xc-. In addition, activated microglial cells act to block glutamate transporters in oligodendrocytes, leading to a net increase in extracellular glutamate and subsequent oligodendrocyte death. The blocking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors or the system xc- antiporter prevented the oligodendrocyte injury produced by exposure to LPS-activated microglial cells in mixed glial cultures. In a whole-mount rat optic nerve, LPS exposure produced wide-spread oligodendrocyte injury that was prevented by AMPA/kainate receptor block and greatly reduced by a system xc- antiporter block. The cell death was typified by swelling and disruption of mitochondria, a feature that was not found in closely associated axonal mitochondria. Our results reveal a novel mechanism by which reactive microglia can contribute to altering glutamate homeostasis and to the pathogenesis of white matter disorders.
Insights
Reactive microglia disrupt glutamate homeostasis, causing oligodendrocyte death in white matter disorders. Blocking alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or system xc- prevents this injury.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Elevated extracellular glutamate leads to excitotoxic oligodendrocyte death, contributing to demyelination in white matter disorders like multiple sclerosis.
- The precise mechanisms altering glutamate homeostasis in these conditions are not fully understood.
Purpose of the Study:
- To investigate how microglial cells influence glutamate homeostasis and contribute to oligodendrocyte injury.
- To elucidate the role of microglial activation in the pathogenesis of white matter disorders.
Main Methods:
- Utilized cultured oligodendrocytes and mixed glial cultures exposed to activated microglial cells.
- Employed whole-mount rat optic nerve models with lipopolysaccharide (LPS) exposure.
- Assessed the impact of blocking alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors and the cystine-glutamate antiporter system xc-.
Main Results:
- Activated microglia compromise oligodendrocyte glutamate homeostasis by releasing glutamate via system xc- and blocking oligodendrocyte glutamate transporters.
- This leads to increased extracellular glutamate and subsequent oligodendrocyte death, characterized by mitochondrial swelling.
- Inhibition of AMPA/kainate receptors or system xc- prevented microglial-induced oligodendrocyte injury in vitro and in vivo.
Conclusions:
- Reactive microglia play a significant role in altering glutamate homeostasis, contributing to oligodendrocyte death and white matter damage.
- Targeting microglial activity, specifically system xc- and AMPA/kainate receptors, offers potential therapeutic strategies for white matter disorders.
