Interleukin-1β Alters Hebbian Synaptic Plasticity in Multiple Sclerosis

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

doi:10.3390/ijms21196982

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.

Highlights

Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammation of the central nervous system (CNS), which is associated with demyelinating white matter lesions and neurodegeneration
To better characterize how IL-1β could affect long-term potentiation (LTP) in human multiple sclerosis (MS), we investigated in a group of RR-MS patients the effect of IL-1β on LTP induction using paired associative stimulation (PAS)
Repeated low-frequency electrical stimulation of the median nerve followed 25 ms after by single-pulse transcranial magnetic stimulation (TMS) over the cortical representation of the contralateral abductor pollicis brevis (APB) muscle is able to increase the amplitude of the motor-evoked potential (MEP) in the APB muscle, persisting up to 60 min

Summary

Introduction

Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammation of the central nervous system (CNS), which is associated with demyelinating white matter lesions and neurodegeneration. Long-term potentiation (LTP), is one of the main physiological mechanisms involved in clinical recovery after brain damage [1,2]. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and in patients with MS, have shown that CNS inflammation affects synaptic functioning. Specific proinflammatory mediators released by the immune cells influence synaptic transmission and plasticity. Experimental studies in EAE have demonstrated that IL-1β alters synaptic functioning, promoting synaptic hyperexcitability and glutamate-mediated excitotoxicity [8,9]. Raised IL-1β signaling has been associated with worse disease course and increased neurodegeneration in EAE and in patients with MS [10,11]

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Methods

Conclusion