Glutamate receptor expression in multiple sclerosis lesions.

Abstract

Blockade of receptors for the excitatory neurotransmitter glutamate ameliorates neurological clinical signs in models of the CNS inflammatory demyelinating disease multiple sclerosis (MS). To investigate whether glutamate excitoxicity may play a role in MS pathogenesis, the cellular localization of glutamate and its receptors, transporters and enzymes was examined. Expression of glutamate receptor (GluR) 1, a Ca(++)-permeable ionotropic AMPA receptor subunit, was up-regulated on oligodendrocytes in active MS lesion borders, but Ca(++)-impermeable AMPA GluR2 subunit levels were not increased. Reactive astrocytes in active plaques expressed AMPA GluR3 and metabotropic mGluR1, 2/3 and 5 receptors and the GLT-1 transporter, and a subpopulation was immunostained with glutamate antibodies. Activated microglia and macrophages were immunopositive for GluR2, GluR4 and NMDA receptor subunit 1. Kainate receptor GluR5-7 immunostaining showed endothelial cells and dystrophic axons. Astrocyte and macrophage populations expressed glutamate metabolizing enzymes and unexpectedly the EAAC1 transporter, which may play a role in glutamate uptake in lesions. Thus, reactive astrocytes in MS white matter lesions are equipped for a protective role in sequestering and metabolizing extracellular glutamate. However, they may be unable to maintain glutamate at levels low enough to protect oligodendrocytes rendered vulnerable to excitotoxic damage because of GluR1 up-regulation.

• Authors: Jia Newcombe, Alim Uddin, Rosamund Dove, Bela Patel, Lechoslaw Turski, Yukio Nishizawa, Terence Smith
• Journal: Brain pathology (Zurich, Switzerland) (Brain Pathol) Vol. 18 Issue 1 Pg. 52-61 (Jan 2008) ISSN: 1015-6305 [Print] Switzerland
• PMID: 17924980 (Publication Type: Journal Article)

Chemical References

• Excitatory Amino Acid Transporter 3
• Neurotoxins
• Protein Subunits
• Receptors, AMPA
• Receptors, Kainic Acid
• SLC1A1 protein, human
• Vesicular Glutamate Transport Proteins
• Glutamic Acid

Topics

• Adult
• Aged
• Aged, 80 and over
• Astrocytes (metabolism, pathology)
• Central Nervous System (metabolism, pathology, physiopathology)
• Excitatory Amino Acid Transporter 3 (metabolism)
• Female
• Gliosis (metabolism, pathology, physiopathology)
• Glutamic Acid (metabolism)
• Humans
• Macrophages (metabolism, pathology)
• Male
• Middle Aged
• Multiple Sclerosis (metabolism, pathology, physiopathology)
• Nerve Fibers, Myelinated (metabolism, pathology)
• Neuroglia (metabolism, pathology)
• Neurotoxins (metabolism)
• Oligodendroglia (metabolism, pathology)
• Protein Subunits (metabolism)
• Receptors, AMPA (metabolism)
• Receptors, Kainic Acid (metabolism)
• Vesicular Glutamate Transport Proteins (metabolism)