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Glutamate excitotoxicity inflicts paranodal myelin splitting and retraction

Yan Fu1, Wenjing Sun, Yunzhou Shi

  • 1Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.

Plos One
|August 21, 2009
PubMed

Insights

Glutamate damages myelin in the brain by breaking connections and activating calcium, leading to nerve signal loss. Blocking calcium or specific receptors can prevent this white matter injury.

Area of Science:

  • Neuroscience
  • Neurobiology
  • Cellular Biology

Background:

  • Paranodal myelin damage is a hallmark of white matter injury, but its cause is unclear.
  • Understanding the mechanisms of myelin damage is crucial for treating neurological disorders.

Purpose of the Study:

  • To identify the molecular mechanisms underlying glutamate-induced paranodal myelin damage.
  • To investigate the role of calcium ions and specific glutamate receptors in this process.

Main Methods:

  • Coherent anti-Stokes Raman scattering (CARS) and multimodal multiphoton imaging were used to visualize myelin sheath and axo-glial junctions.
  • Compound action potentials were measured to assess axonal conduction.
  • Pharmacological agents, including a potassium channel blocker, calcium ionophore, calpain inhibitor, and glutamate receptor modulators, were employed.

Main Results:

  • Glutamate application caused significant paranodal myelin splitting and retraction, breaking axo-glial junctions and exposing K+ channels.
  • This led to axonal conduction deficits, which were partially restored by 4-aminopyridine.
  • Calcium ionophore induced similar myelin retraction, which was prevented by calcium exclusion or calpain inhibition.
  • NMDA and kainate receptors were identified as mediators of glutamate-induced myelin damage.

Conclusions:

  • Elevated glutamate levels in diseased white matter can impair paranodal myelin.
  • This damage is mediated by NMDA and kainate receptor activation, leading to calcium overload and calpain activation.
  • Targeting these pathways may offer therapeutic strategies for white matter injuries.

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