Present address of GG: Department of Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.
Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis
Version of Record online: 20 DEC 2012
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Endothelin. Guest Editors: Anthony P Davenport and Matthias Barton
Volume 168, Issue 2, pages 502–517, January 2013
How to Cite
Grasselli, G., Rossi, S., Musella, A., Gentile, A., Loizzo, S., Muzio, L., Di Sanza, C., Errico, F., Musumeci, G., Haji, N., Fresegna, D., Sepman, H., De Chiara, V., Furlan, R., Martino, G., Usiello, A., Mandolesi, G. and Centonze, D. (2013), Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis. British Journal of Pharmacology, 168: 502–517. doi: 10.1111/j.1476-5381.2012.02178.x
These authors are equally contributing first authors.
- Issue online: 20 DEC 2012
- Version of Record online: 20 DEC 2012
- Accepted manuscript online: 24 AUG 2012 08:06AM EST
- Manuscript Accepted: 13 AUG 2012
- Manuscript Revised: 4 AUG 2012
- Manuscript Received: 3 JAN 2012
- Italian National Ministero della Salute
- Fondazione TERCAS to DC
- Fondazione Italiana Sclerosi Multipla (FISM) to SR
- European Community
- multiple sclerosis;
Background and Purpose
Glutamate transmission is dysregulated in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the animal model of MS. A characteristic of EAE is increased glutamate transmission associated with up-regulation of AMPA receptors. However, little is known about the role of NMDA receptors in the synaptic modifications induced by EAE.
The contribution of NMDA receptors to the alterations of glutamate transmission and disease severity in EAE mice was assessed by means of neurophysiological, morphological, Western blot, metabolic and clinical score assessments.
In our EAE mice, there was an NMDA receptor-dependent increase of glutamate release, associated with marked activation of the astroglia. Presynaptic NMDA receptors became overactive during EAE, increasing synaptic glutamate release by a mechanism dependent on voltage-gated sodium channels. By means of NAD(P)H autofluorescence analysis, we also found that EAE has a glutamate and NMDA receptor-dependent dysfunction of mitochondrial activity, which is known to contribute to the neurodegenerative damage of MS and EAE. Furthermore, pharmacological blockade of NMDA receptors in vivo ameliorated both synaptic transmission defects and of the clinical disease course of EAE mice, while EAE induced in mice with a genetically enhanced NMDA receptor signalling had opposite effects.
Conclusions and Implications
Our data, showing both sensitization of NMDA receptors and their involvement in the progression of the EAE disease, supggest that pharmacological impairment of NMDA receptor signalling would be a component of a neuroprotection strategy in MS.