title: Synaptic plasticity and PDGF signaling defects underlie clinical progression in multiple sclerosis.
abstract: Neuroplasticity is essential to prevent clinical worsening despite continuing neuronal loss in several brain diseases, including multiple sclerosis (MS). The precise nature of the adaptation mechanisms taking place in MS brains, ensuring protection from disability appearance and accumulation, is however unknown. Here, we explored the hypothesis that long-term synaptic potentiation (LTP), potentially able to minimize the effects of neuronal loss by providing extra excitation of denervated neurons, is the most relevant form of adaptive plasticity in stable MS patients, and it is disrupted in progressing MS patients. We found that LTP, explored by means of transcranial magnetic theta burst stimulation over the primary motor cortex, was still possible, and even favored, in stable relapsing-remitting (RR-MS) patients, whereas it was absent in individuals with primary progressive MS (PP-MS). We also provided evidence that platelet-derived growth factor (PDGF) plays a substantial role in favoring both LTP and brain reserve in MS patients, as this molecule: (1) was reduced in the CSF of PP-MS patients, (2) enhanced LTP emergence in hippocampal mouse brain slices, (3) was associated with more pronounced LTP in RR-MS patients, and (4) was associated with the clinical compensation of new brain lesion formation in RR-MS. Our results show that brain plasticity reserve, in the form of LTP, is crucial to contrast clinical deterioration in MS. Enhancing PDGF signaling might represent a valuable treatment option to maintain brain reserve and to attenuate the clinical consequences of neuronal damage in the progressive phases of MS and in other neurodegenerative disorders.
authors.affiliation: Istituto Di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, 00143 Rome, Italy, Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, 00133 Rome, Italy, Dipartimento di Fisiologia e Farmacologia, Università di Roma La Sapienza, 00185, Rome, Italy, Laboratorio di Farmacologia della Plasticità Sinaptica, European Brain Research Institute, 00143 Rome, Italy, and Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mori
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Sonia
authors.initials: S
authors.lastname: Piccinin
authors.forename: Caterina
authors.initials: C
authors.lastname: Motta
authors.forename: Dalila
authors.initials: D
authors.lastname: Mango
authors.forename: Hajime
authors.initials: H
authors.lastname: Kusayanagi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bergami
authors.forename: Valeria
authors.initials: V
authors.lastname: Studer
authors.forename: Carolina G
authors.initials: CG
authors.lastname: Nicoletti
authors.forename: Fabio
authors.initials: F
authors.lastname: Buttari
authors.forename: Francesca
authors.initials: F
authors.lastname: Barbieri
authors.forename: Nicola B
authors.initials: NB
authors.lastname: Mercuri
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
authors.forename: Roberto
authors.initials: R
authors.lastname: Furlan
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000502:physiology; D002540:Cerebral Cortex / Q000502:physiology; D018450:Disease Progression; D004558:Electric Stimulation; D055724:Electrophysiological Phenomena; D005071:Evoked Potentials / Q000502:physiology; D005260:Female; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000503:physiopathology*; D020528:Multiple Sclerosis, Chronic Progressive / Q000134:cerebrospinal fluid / Q000503:physiopathology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000134:cerebrospinal fluid / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000134:cerebrospinal fluid / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D013826:Theta Rhythm / Q000502:physiology; D050781:Transcranial Magnetic Stimulation
chemical_list: D010982:Platelet-Derived Growth Factor