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  • Review Article
  • Published:

Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis

Nature Reviews Neurology volume 11, pages 711–724 (2015)Cite this article

Subjects

Key Points

  • Progressive synaptic loss and dysfunction—also known as synaptopathy—occur early in multiple sclerosis (MS), and in experimental autoimmune encephalomyelitis (EAE), which is used to study MS in rodent models

  • Along with demyelination and axonal damage or transection, synaptopathy is a pathophysiological hallmark observed in MS and EAE; moreover, it is independent of axonal transection and demyelination

  • Synaptopathy has long-lasting effects that can be detrimental for motor and cognitive functions

  • In MS and EAE, neuroinflammation alters the balance between the GABAergic and glutamatergic systems in the brain and spinal cord

  • Proinflammatory cytokines released during acute MS attacks increase glutamate-mediated synaptic transmission and reduce γ-aminobutyric acid-mediated synaptic signalling, resulting in unbalanced synaptic hyperexcitation and possibly also to neurodegeneration

  • Targeting of mechanisms that stabilize, protect, repair or help regenerate synapses would enable clinical intervention at both early and late stages of the disease

Abstract

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.

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Figure 1: Inflammatory synaptopathy in MS and EAE.
Figure 2: Demyelination, axonal loss and synaptopathy characterize multiple sclerosis and experimental autoimmune encephalomyelitis pathophysiology.
Figure 3: Cascades leading to inflammation-induced excitotoxicity.

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Acknowledgements

This work was supported by the Italian National Ministero della Salute (Progetto Giovani Ricercatori) to G.M. (No. GR-2011-02347036) and A.M. (No. GR-2011-02351422) and by Fondazione Italiana Sclerosi Multipla (No. FISM 2010/S/2) to D.C.

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Authors and Affiliations

  1. IRCCS Fondazione Santa Lucia/Centro Europeo per la Ricerca sul Cervello (CERC), Via del Fosso di Fiorano 64, Rome, 00143, Italy

    Georgia Mandolesi, Alessandra Musella, Diego Fresegna, Silvia Bullitta & Helena Sepman

  2. Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Via Montpellier 1, Rome, 00133, Italy

    Antonietta Gentile, Francesca De Vito, Helena Sepman & Girolama A. Marfia

  3. IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Via Atinense 18, Pozzilli, 86077, Italy

    Diego Centonze

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  1. Georgia Mandolesi
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Contributions

D.C., G.M., A.G., A.M., D.F., F.D.V., S.B. and H.S. researched data for the article. D.C. and G.M. wrote the article. D.C., G.M., A.G., A.M. and G.A.M. provided substantial contributions to discussion of content. All authors participated in reviewing and/or editing of the manuscript before submission.

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Correspondence to Diego Centonze.

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Competing interests

D.C. is an Advisory Board member for Bayer Schering, Merck-Serono and Teva, and has received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen Idec, Genzyme, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi-Aventis and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen Idec, Novartis, Merck Serono, Sanofi-Aventis and Teva. The other authors declare no competing interests.

Supplementary information

Supplementary Table 1

Evidence for glutamatergic system dysfunction in MS (DOCX 34 kb)

Supplementary Table 2

Evidence for glutamatergic system dysfunction in EAE (DOCX 33 kb)

Supplementary Table 3

Evidence for GABAergic system dysfunction in MS and EAE (DOCX 29 kb)

Supplementary Table 4

Inflammation-dependent synaptic dysfunction in EAE models of MS (DOCX 61 kb)

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Mandolesi, G., Gentile, A., Musella, A. et al. Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. Nat Rev Neurol 11, 711–724 (2015). https://doi.org/10.1038/nrneurol.2015.222

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