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Interleukin-1β Promotes Long-Term Potentiation in Patients with Multiple Sclerosis

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Abstract

The immune system shapes synaptic transmission and plasticity in experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis (MS). These synaptic adaptations are believed to drive recovery of function after brain lesions, and also learning and memory deficits and excitotoxic neurodegeneration; whether inflammation influences synaptic plasticity in MS patients is less clear. In a cohort of 59 patients with MS, we found that continuous theta-burst transcranial magnetic stimulation did not induce the expected long-term depression (LTD)-like synaptic phenomenon, but caused persisting enhancement of brain cortical excitability. The amplitude of this long-term potentiation (LTP)-like synaptic phenomenon correlated with the concentration of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the cerebrospinal fluid. In MS and EAE, the brain and spinal cord are typically enriched of CD3+ T lymphocyte infiltrates, which are, along with activated microglia and astroglia, a major cause of inflammation. Here, we found a correlation between the presence of infiltrating T lymphocytes in the hippocampus of EAE mice and synaptic plasticity alterations. We observed that T lymphocytes from EAE, but not from control mice, release IL-1β and promote LTP appearance over LTD, thereby mimicking the facilitated LTP induction observed in the cortex of MS patients. EAE-specific T lymphocytes were able to suppress GABAergic transmission in an IL-1β-dependent manner, providing a possible synaptic mechanism able to lower the threshold of LTP induction in MS brains. Moreover, in vivo blockade of IL-1β signaling resulted in inflammation and synaptopathy recovery in EAE hippocampus. These data provide novel insights into the pathophysiology of MS.

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Acknowledgments

This investigation was supported by Fondazione Italiana Sclerosi Multipla (Progetto Speciale FISM), by the Italian National Ministry of Health and by the Italian National Ministry of University to DC. We are indebted to Dr. Mauro Federici and Vladimiro Batocchi for excellent technical assistance.

Conflict of interest

Diego Centonze acted as an Advisory Board member of Merck Serono, Teva, Bayer Schering, Biogen Idec, Novartis, and received funding for traveling and honoraria for speaking or consultation fees from Merck Serono, Teva, Novartis, Bayer Schering, Sanofi-aventis, Biogen Idec. He is also the principal investigator in clinical trials for Novartis, Merck Serono, Teva, Bayer Schering, Sanofi-aventis, Biogen Idec, Roche. The other authors have no disclosures to report.

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Authors and Affiliations

  1. IRCSS Fondazione Santa Lucia, 00143, Rome, Italy

    Francesco Mori, Robert Nisticò, Georgia Mandolesi, Dalila Mango, Hajime Kusayanagi, Nicola Berretta, Antonietta Gentile, Alessandra Musella, Carolina G. Nicoletti, Fabio Buttari, Nicola B. Mercuri & Diego Centonze

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

    Francesco Mori, Georgia Mandolesi, Dalila Mango, Hajime Kusayanagi, Antonietta Gentile, Alessandra Musella, Carolina G. Nicoletti, Fabio Buttari, Nicola B. Mercuri & Diego Centonze

  3. Dipartimento di Fisiologia e Farmacologia, Università di Roma “La Sapienza”, 00185, Rome, Italy

    Robert Nisticò, Sonia Piccinin & Ferdinando Nicoletti

  4. Laboratorio di Farmacologia della Plasticità Sinaptica, European Brain Research Institute (EBRI), 00143, Rome, Italy

    Sonia Piccinin

  5. Neuroimmunology Unit, Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, 20132, Milan, Italy

    Alessandra Bergami, Gianvito Martino & Roberto Furlan

  6. IRCCS Neuromed, 86077, Pozzilli, Italy

    Ferdinando Nicoletti

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  1. Francesco Mori
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Correspondence to Diego Centonze.

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Francesco Mori and Robert Nisticò are equally contributing first authors.

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Mori, F., Nisticò, R., Mandolesi, G. et al. Interleukin-1β Promotes Long-Term Potentiation in Patients with Multiple Sclerosis. Neuromol Med 16, 38–51 (2014). https://doi.org/10.1007/s12017-013-8249-7

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