Francesco Mori1, Robert Nisticò2, Carolina G Nicoletti3, Sara Zagaglia4, Georgia Mandolesi5, Sonia Piccinin6, Gianvito Martino7, Annamaria Finardi7, Paolo M Rossini8, Girolama A Marfia1, Roberto Furlan7, Diego Centonze9. 1. Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy/IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, Italy. 2. Dipartimento di Biologia, Università degli Studi di Roma Tor Vergata, Roma, Italy/Laboratorio di Farmacologia della Plasticità Sinaptica, EBRI-European Brain Research Institute, Roma, Italy. 3. Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy/IRCCS Fondazione Santa Lucia, Roma, Italy. 4. Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy/Clinica di Neurologia, Università Politecnica delle Marche, Ancona, Italy. 5. IRCCS Fondazione Santa Lucia, Roma, Italy. 6. Laboratorio di Farmacologia della Plasticità Sinaptica, EBRI-European Brain Research Institute, Roma, Italy. 7. Neuroimmunology Unit, Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, Milano, Italy. 8. Institute of Neurology, Catholic University, Rome, Italy/Brain Connectivity Laboratory, IRCCS San Raffaele Pisana, Rome, Italy. 9. Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy/IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli, Italy centonze@uniroma2.it.
Abstract
BACKGROUND: Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease. OBJECTIVE: To assess the role of RANTES in the regulation of cortical excitability. METHODS: We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro. RESULTS: CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1β. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP. CONCLUSION: RANTES correlates with inflammation and synaptic excitability in MS brains.
BACKGROUND: Alterations of synaptic transmission induced by inflammatory activity have been linked to the pathogenic mechanisms of multiple sclerosis (MS). Regulated upon activation, normal T-cell expressed, and secreted (RANTES) is a pro-inflammatory chemokine involved in MS pathophysiology, potentially able to regulate glutamate release and plasticity in MS brains, with relevant consequences on the clinical manifestations of the disease. OBJECTIVE: To assess the role of RANTES in the regulation of cortical excitability. METHODS: We explored the association of RANTES levels in the cerebrospinal fluid (CSF) of newly diagnosed MS patients with magnetic resonance imaging (MRI) and laboratory measures of inflammatory activity, as well its role in the control of cortical excitability and plasticity explored by means of transcranial magnetic stimulation (TMS), and in hippocampal mouse slices in vitro. RESULTS: CSF levels of RANTES were remarkably high only in active MS patients and were correlated with the concentrations of interleukin-1β. RANTES levels were associated with TMS measures of cortical synaptic excitability, but not with long-term potentiation (LTP)-like plasticity. Similar findings were obtained in mouse hippocampal slices in vitro, where we observed that RANTES enhanced basal excitatory synaptic transmission with no effect on LTP. CONCLUSION:RANTES correlates with inflammation and synaptic excitability in MS brains.
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