Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis.
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 r...
Main Authors: | , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2013-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC3696106?pdf=render |
_version_ | 1811267267278667776 |
---|---|
author | Silvia Rossi Valeria Studer Alessandro Moscatelli Caterina Motta Giancarlo Coghe Giuseppe Fenu Stacy Caillier Fabio Buttari Francesco Mori Francesca Barbieri Maura Castelli Valentina De Chiara Fabrizia Monteleone Raffaele Mancino Giorgio Bernardi Sergio E Baranzini Maria G Marrosu Jorge R Oksenberg Diego Centonze |
author_facet | Silvia Rossi Valeria Studer Alessandro Moscatelli Caterina Motta Giancarlo Coghe Giuseppe Fenu Stacy Caillier Fabio Buttari Francesco Mori Francesca Barbieri Maura Castelli Valentina De Chiara Fabrizia Monteleone Raffaele Mancino Giorgio Bernardi Sergio E Baranzini Maria G Marrosu Jorge R Oksenberg Diego Centonze |
author_sort | Silvia Rossi |
collection | DOAJ |
description | 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. |
first_indexed | 2024-04-12T20:59:22Z |
format | Article |
id | doaj.art-ac849ca193ad4a9c8c5893d2677a3459 |
institution | Directory Open Access Journal |
issn | 1932-6203 |
language | English |
last_indexed | 2024-04-12T20:59:22Z |
publishDate | 2013-01-01 |
publisher | Public Library of Science (PLoS) |
record_format | Article |
series | PLoS ONE |
spelling | doaj.art-ac849ca193ad4a9c8c5893d2677a34592022-12-22T03:16:53ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0186e6735710.1371/journal.pone.0067357Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis.Silvia RossiValeria StuderAlessandro MoscatelliCaterina MottaGiancarlo CogheGiuseppe FenuStacy CaillierFabio ButtariFrancesco MoriFrancesca BarbieriMaura CastelliValentina De ChiaraFabrizia MonteleoneRaffaele MancinoGiorgio BernardiSergio E BaranziniMaria G MarrosuJorge R OksenbergDiego CentonzeSynaptic 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.http://europepmc.org/articles/PMC3696106?pdf=render |
spellingShingle | Silvia Rossi Valeria Studer Alessandro Moscatelli Caterina Motta Giancarlo Coghe Giuseppe Fenu Stacy Caillier Fabio Buttari Francesco Mori Francesca Barbieri Maura Castelli Valentina De Chiara Fabrizia Monteleone Raffaele Mancino Giorgio Bernardi Sergio E Baranzini Maria G Marrosu Jorge R Oksenberg Diego Centonze Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis. PLoS ONE |
title | Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis. |
title_full | Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis. |
title_fullStr | Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis. |
title_full_unstemmed | Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis. |
title_short | Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis. |
title_sort | opposite roles of nmda receptors in relapsing and primary progressive multiple sclerosis |
url | http://europepmc.org/articles/PMC3696106?pdf=render |
work_keys_str_mv | AT silviarossi oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT valeriastuder oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT alessandromoscatelli oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT caterinamotta oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT giancarlocoghe oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT giuseppefenu oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT stacycaillier oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT fabiobuttari oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT francescomori oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT francescabarbieri oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT mauracastelli oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT valentinadechiara oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT fabriziamonteleone oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT raffaelemancino oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT giorgiobernardi oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT sergioebaranzini oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT mariagmarrosu oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT jorgeroksenberg oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis AT diegocentonze oppositerolesofnmdareceptorsinrelapsingandprimaryprogressivemultiplesclerosis |