Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis

Georgia Mandolesi, Antonietta Gentile, Alessandra Musella, Diego Fresegna, Francesca De Vito, Silvia Bullitta, Helena Sepman, Girolama A. Marfia, Diego Centonze

Research output: Contribution to journalArticlepeer-review


Multiple sclerosis (MS) has long been regarded as a chronic inflammatory disease of the white matter that leads to demyelination and eventually to neurodegeneration. In the past decade, several aspects of MS pathogenesis have been challenged, and degenerative changes of the grey matter, which are independent of demyelination, have become a topic of interest. CNS inflammation in MS and experimental autoimmune encephalomyelitis (EAE; a disease model used to study MS in rodents) causes a marked imbalance between GABAergic and glutamatergic transmission, and a loss of synapses, all of which leads to a diffuse 'synaptopathy'. Altered synaptic transmission can occur early in MS and EAE, independently of demyelination and axonal loss, and subsequently causes excitotoxic damage. Inflammation-driven synaptic abnormalities are emerging as a prominent pathogenic mechanism in MS-importantly, they are potentially reversible and, therefore, represent attractive therapeutic targets. In this Review, we focus on the connection between inflammation and synaptopathy in MS and EAE, which sheds light not only on the pathophysiology of MS but also on that of primary neurodegenerative disorders in which inflammatory processes contribute to disease progression.

Original languageEnglish
Pages (from-to)711-724
Number of pages14
JournalNature Reviews Neurology
Issue number12
Publication statusPublished - Dec 1 2015

ASJC Scopus subject areas

  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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