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Clinical Trial
. 2020 Sep 23;21(19):6982.
doi: 10.3390/ijms21196982.

Interleukin-1β Alters Hebbian Synaptic Plasticity in Multiple Sclerosis

Mario Stampanoni Bassi  1 , Fabio Buttari  1 , Carolina Gabri Nicoletti  2 , Francesco Mori  2 , Luana Gilio  1 , Ilaria Simonelli  3 , Nicla De Paolis  1 , Girolama Alessandra Marfia  1   2 , Roberto Furlan  4 , Annamaria Finardi  4 , Diego Centonze  1   2 , Ennio Iezzi  1
Affiliations
Clinical Trial

Interleukin-1β Alters Hebbian Synaptic Plasticity in Multiple Sclerosis

Mario Stampanoni Bassi et al. Int J Mol Sci. .

Abstract

In multiple sclerosis (MS), inflammation alters synaptic transmission and plasticity, negatively influencing the disease course. In the present study, we aimed to explore the influence of the proinflammatory cytokine IL-1β on peculiar features of associative Hebbian synaptic plasticity, such as input specificity, using the paired associative stimulation (PAS). In 33 relapsing remitting-MS patients and 15 healthy controls, PAS was performed on the abductor pollicis brevis (APB) muscle. The effects over the motor hot spot of the APB and abductor digiti minimi (ADM) muscles were tested immediately after PAS and 15 and 30 min later. Intracortical excitability was tested with paired-pulse transcranial magnetic stimulation (TMS). The cerebrospinal fluid (CSF) levels of IL-1β were calculated. In MS patients, PAS failed to induce long-term potentiation (LTP)-like effects in the APB muscle and elicited a paradoxical motor-evoked potential (MEP) increase in the ADM. IL-1β levels were negatively correlated with the LTP-like response in the APB muscle. Moreover, IL-1β levels were associated with synaptic hyperexcitability tested with paired-pulse TMS. Synaptic hyperexcitability caused by IL-1β may critically contribute to alter Hebbian plasticity in MS, inducing a loss of topographic specificity.

Keywords: interleukin (IL)-1β; long-term potentiation (LTP); multiple sclerosis (MS); paired associative stimulation (PAS); synaptic plasticity; transcranial magnetic stimulation (TMS).

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Conflict of interest statement

The authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Fabio Buttari acted as Advisory Board members of Teva and Roche and received honoraria for speaking or consultation fees from Merck Serono, Teva, Biogen Idec, Sanofi, and Novartis and non-financial support from Merck Serono, Teva, Biogen Idec, and Sanofi. Girolama Alessandra Marfia received honoraria for speaking, consultation fees, and travel funding from Roche, Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, Mylan, and Teva. She is the principal investigator in clinical trials for Actelion, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, Teva. Roberto Furlan has received honoraria as a speaker or for research support from Biogen, Novartis, Merck, Roche, Genzyme. Diego Centonze is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Mario Stampanoni Bassi, Carolina Gabri Nicoletti, Francesco Mori, Luana Gilio, Ilaria Simonelli, Nicla De Paolis, Annamaria Finardi, Ennio Iezzi declare no conflict of interest.

Figures

Figure 1
Figure 1
PAS Effects in RR-MS Patients and Controls. Figure 1 legend. In healthy subjects, PAS elicited the expected homosynaptic LTP-like effect in the APB muscle (left panel), whereas in MS patients, PAS elicited heterosynaptic LTP in the ADM muscle (right panel). * p ≤ 0.05; ** p ≤0.01. The p values refer to the comparisons between pre and post 0, post 15, and post 30 in each muscle. All p values were adjusted by Benjamini–Hochberg correction. Abbreviations: APB (abductor pollicis brevis); ADM (abductor digiti minimi); MEP (motor-evoked potential); PAS (paired associative stimulation); RR-MS (relapsing-remitting multiple sclerosis).
Figure 2
Figure 2
Correlation between IL-1β CSF Levels and PAS Effects. Figure 2 legend. A negative correlation was found between IL-1β CSF concentrations and LTP-like effects in the APB muscle at post 0, post 15, and post 30 (upper panels); conversely, no significant correlation emerged with LTP-like effects in the ADM muscle (middle panels). A significant negative correlation was found between IL-1β CSF levels and the ratio of the LTP-like effect induced in APB and ADM muscles (lower panels). Abbreviations: APB (abductor pollicis brevis); ADM (abductor digiti minimi); CSF (cerebrospinal fluid); IL (interleukin); MEP (motor-evoked potential).
Figure 3
Figure 3
IL-1β CSF Detectability and PAS Effects. Figure 3 legend. In the IL-1β negative group, PAS failed to induce LTP-like effects in both APB and ADM muscles (left panel), whereas in the IL-1β positive group, PAS elicited an abnormal LTP in the ADM muscle (right panel). * p ≤ 0.05. The p values refer to the comparisons between pre and post 0, post 15, and post 30 in each muscle. All p values were adjusted by Benjamini–Hochberg correction. Abbreviations: APB (abductor pollicis brevis); ADM (abductor digiti minimi); CSF (cerebrospinal fluid); IL (interleukin); PAS (paired associative stimulation).
Figure 4
Figure 4
Correlation between IL-1β CSF Levels and Inhibitory/Excitatory Intracortical Transmission. Figure 4 legend. IL-1β CSF levels positively correlated with reduced intracortical inhibition (left panel) and increased intracortical facilitation (right panel). Abbreviations: CSF (cerebrospinal fluid); ICF (intracortical facilitation); IL (interleukin); MEP (motor-evoked potential); SICI (short-interval intracortical inhibition).
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