The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis

D. Centonze, L. Muzio, S. Rossi, R. Furlan, G. Bernardi, G. Martino

Research output: Contribution to journalArticle

Abstract

Multiple sclerosis (MS) has been classically regarded as a disorder of the white matter of the central nervous system (CNS). However, early alterations of the neuronal compartment occurring in this disorder are partially independent of demyelination. Soluble inflammatory cytokines and glutamate have been proposed as major determinants of neurodegeneration in MS as well as in its experimental animal model, namely experimental autoimmune encephalomyelitis (EAE). The relationship between these two major determinants has been largely elusive. In recent years, unexpected connections have emerged between immune cells and soluble cytokines on the one hand, and synaptic transmission and neurodegeneration on the other. Neurophysiological recordings have recently shown that glutamate-mediated excitatory postsynaptic currents are enhanced during the early phase of EAE, because of altered expression and phosphorylation of AMPA receptors and the downregulation of the immediate early gene Arc/Arg3.1. The synaptic alterations occurring during neuroinflammatory diseases are largely mediated by inflammatory cytokines released from infiltrating T cells and from activated microglia, and are responsible, at least in part, for irreversible dendritic pathology. Collectively, the data covered in this review article suggest that CNS-confined inflammation in MS is associated with the release of soluble molecules, which are capable of altering excitatory synaptic transmission and, finally, of stimulating secondary neurodegenerative gray matter pathology.

Original languageEnglish
Pages (from-to)1083-1091
Number of pages9
JournalCell Death and Differentiation
Volume17
Issue number7
DOIs
Publication statusPublished - Jul 2010

Keywords

  • AMPA receptors
  • Arc/Arg3.1
  • Excitotoxicity
  • Experimental autoimmune encephalomyelitis
  • Microglia
  • TNFα

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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