Concentrations of glutamate released following spinal cord injury kill oligodendrocytes in the spinal cord
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Published on: February 5, 2015
Guo-Ying Xu1, Michael G Hughes, Zaiming Ye
1Department of Neurosciences and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-1043, USA.
Abstract:
We investigated in vivo in rats whether sufficient glutamate is released following spinal cord injury (SCI) to kill oligodendrocytes. Microdialysis sampling was used to establish the level of glutamate released (550 +/- 80 microM) in the white matter during SCI. This glutamate concentration was administered into the spinal cords of other rats and the densities of oligodendrocytes remaining 24 and 72 h later determined by counting cells immunostained with the oligodendrocyte marker CC-1. Administration of ACSF, 4.0 mM glutamate (estimated resulting tissue exposure 500 microM) and 10.0 mM glutamate by microdialysis reduced oligodendrocyte density 22%, 57%, and 74%, respectively, relative to normal at 24 h post-exposure. Therefore, sufficient glutamate is released following SCI to damage white matter. Oligodendrocyte densities near the fiber track were not significantly different at 72 h from 24 h post-exposure, so most glutamate-induced oligodendrocyte death occurs within 24 h after exposure. Injecting the AMPA/kainate receptor blocker NBQX into the spinal cord during glutamate administration reduced the glutamate-induced decrease in oligodendrocyte density, evidence for AMPA/kainate receptor involvement in glutamate-induced oligodendrocyte death. This work directly demonstrates in vivo that following SCI glutamate reaches concentrations toxic to white matter and that AMPA/kainate receptors mediate this glutamate toxicity to oligodendrocytes.
Insights
Following spinal cord injury (SCI), high glutamate levels in the white matter are toxic to oligodendrocytes. AMPA/kainate receptors mediate this glutamate-induced cell death, occurring primarily within 24 hours.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Spinal cord injury (SCI) can lead to secondary damage.
- Oligodendrocytes are crucial for white matter integrity.
- The role of glutamate excitotoxicity in SCI-induced oligodendrocyte death requires further in vivo investigation.
Purpose of the Study:
- To determine if glutamate released during SCI is sufficient to cause oligodendrocyte death in vivo.
- To investigate the time course of glutamate-induced oligodendrocyte death.
- To identify the specific glutamate receptors involved in this toxicity.
Main Methods:
- In vivo microdialysis in rats to measure glutamate levels during SCI.
- Administration of varying glutamate concentrations into the spinal cord.
- Immunohistochemical staining for oligodendrocyte marker CC-1 to quantify cell density at 24 and 72 hours.
- Administration of AMPA/kainate receptor antagonist NBQX.
Main Results:
- Glutamate levels of 550 +/- 80 microM were detected in white matter during SCI.
- Exogenous glutamate administration significantly reduced oligodendrocyte density in a dose-dependent manner (22% at 500 microM, 57% at 4.0 mM, 74% at 10.0 mM).
- Most oligodendrocyte death occurred within 24 hours post-exposure.
- NBQX administration attenuated glutamate-induced oligodendrocyte loss, implicating AMPA/kainate receptors.
Conclusions:
- Glutamate released following SCI reaches concentrations toxic to oligodendrocytes in vivo.
- Glutamate-induced oligodendrocyte death is rapid, primarily occurring within 24 hours.
- AMPA/kainate receptors mediate the excitotoxicity of glutamate to oligodendrocytes after SCI.
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