title: Interleukin-1β promotes long-term potentiation in patients with multiple sclerosis.
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.
authors.affiliation: IRCSS Fondazione Santa Lucia, 00143, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Mori
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.forename: Georgia
authors.initials: G
authors.lastname: Mandolesi
authors.forename: Sonia
authors.initials: S
authors.lastname: Piccinin
authors.forename: Dalila
authors.initials: D
authors.lastname: Mango
authors.forename: Hajime
authors.initials: H
authors.lastname: Kusayanagi
authors.forename: Nicola
authors.initials: N
authors.lastname: Berretta
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bergami
authors.forename: Antonietta
authors.initials: A
authors.lastname: Gentile
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musella
authors.forename: Carolina G
authors.initials: CG
authors.lastname: Nicoletti
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Fabio
authors.initials: F
authors.lastname: Buttari
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: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology; D005260:Female; D005911:Gliosis / Q000209:etiology / Q000473:pathology; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D057967:Infusions, Intraventricular; D053590:Interleukin 1 Receptor Antagonist Protein / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000134:cerebrospinal fluid / Q000503:physiopathology*; D011897:Random Allocation; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D013826:Theta Rhythm; D050781:Transcranial Magnetic Stimulation; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D005680:gamma-Aminobutyric Acid
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