title: Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis.
abstract: Synaptic transmission and plasticity mediated by NMDA receptors (NMDARs) could modulate the severity of multiple sclerosis (MS). Here the role of NMDARs in MS was first explored in 691 subjects carrying specific allelic variants of the NR1 subunit gene or of the NR2B subunit gene of this glutamate receptor. The analysis was replicated for significant SNPs in an independent sample of 1548 MS subjects. The C allele of rs4880213 was found to be associated with reduced NMDAR-mediated cortical excitability, and with increased probability of having more disability than the CT/TT MS subjects. MS severity was higher in the CC group among relapsing-remitting MS (RR-MS) patients, while primary progressive MS (PP-MS) subjects homozygous for the T allele had more pronounced clinical worsening. Mean time to first relapse, but not to an active MRI scan, was lower in the CC group of RR-MS patients, and the number of subjects with two or more clinical relapses in the first two years of the disease was higher in CC compared to CT/TT group. Furthermore, the percentage of relapses associated with residual disability was lower in subjects carrying the T allele. Lesion load at the MRI was conversely unaffected by the C or T allele of this SNP in RR-MS patients. Axonal and neuronal degeneration at the optical coherence tomography was more severe in the TT group of PP-MS patients, while reduced retinal nerve fiber thickness had less consequences on visual acuity in RR-MS patients bearing the T allele. Finally, the T allele was associated with preserved cognitive abilities at the Rao's brief repeatable neuropsychological battery in RR-MS. Signaling through glutamate NMDARs enhances both compensatory synaptic plasticity and excitotoxic neurodegeneration, impacting in opposite ways on RR-MS and PP-MS pathophysiological mechanisms.
authors.affiliation: Clinica Neurologica, Dipartimento di Medicina dei Sistemi, Università Tor Vergata, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Valeria
authors.initials: V
authors.lastname: Studer
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moscatelli
authors.forename: Caterina
authors.initials: C
authors.lastname: Motta
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Coghe
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fenu
authors.forename: Stacy
authors.initials: S
authors.lastname: Caillier
authors.forename: Fabio
authors.initials: F
authors.lastname: Buttari
authors.forename: Francesco
authors.initials: F
authors.lastname: Mori
authors.forename: Francesca
authors.initials: F
authors.lastname: Barbieri
authors.forename: Maura
authors.initials: M
authors.lastname: Castelli
authors.forename: Valentina
authors.initials: V
authors.lastname: De Chiara
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Monteleone
authors.forename: Raffaele
authors.initials: R
authors.lastname: Mancino
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.forename: Maria G
authors.initials: MG
authors.lastname: Marrosu
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D000328:Adult; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology*; D003071:Cognition; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D016015:Logistic Models; D008297:Male; D020528:Multiple Sclerosis, Chronic Progressive / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: C485668:GRIN1 protein, human; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate