Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis

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, 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

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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Effect of SNPs in the…
Figure 1. Effect of SNPs in the GRIN1 and GRIN2B genes on cortical excitability in MS.
Role of A) GRIN1 rs4880213 polymorphism in the regulation of cortical excitability. In subjects carrying the ‘TT’ genotype, SICI was significantly lower than in the other subjects at 2 and 3 ms interstimulus intervals (ISI). No significant effect of B) GRIN2B rs1805247, C) GRIN2B rs7301328 and D) GRIN1rs6293 SNPs was found on SICI/ICF. In the four panels, the x-axis indicates the ISI in ms, the y-axis shows the MEP size elicited by paired-pulse stimulation. * means p

Figure 2. Effect of SNP rs4880213 on…

Figure 2. Effect of SNP rs4880213 on disability progression in MS.

A. The graph shows…

Figure 2. Effect of SNP rs4880213 on disability progression in MS.
A. The graph shows that PI was lower among RR-MS patients with T allele. B. PI was higher among PP-MS subjects homozygous for T allele. C. Disability progression at MSFC was less frequent among RR-MS patients with T allele. D. The graph shows that early disability progression at MSFC (in the first two years of the disease) was more frequent among PP-MS subjects homozygous for T allele. * means p

Figure 3. Effect of SNP rs4880213 on…

Figure 3. Effect of SNP rs4880213 on clinical and MRI measures of inflammatory activity in…

Figure 3. Effect of SNP rs4880213 on clinical and MRI measures of inflammatory activity in MS.
A. The time to first relapse was lower among RR-MS with CC genotype. B. The time to detect inflammatory activity at MRI was similar between CC and CT/TT RR-MS patients. C. ARR, in the first three years of the disease, was lower among RR-MS patients with T allele. D. The graph shows that T2 lesion volume was similar between CC and CT/TT RR-MS patients. ** means p

Figure 4. Effect of SNP rs4880213 on…

Figure 4. Effect of SNP rs4880213 on functional and morphological indexes of neuronal damage in…

Figure 4. Effect of SNP rs4880213 on functional and morphological indexes of neuronal damage in MS.
A. RNFL thickness was similar between CC and CT/TT RR-MS patients. B. RNFL thickness was lower among PP-MS subjects homozygous for T allele. C, D. Correlation analyses between RNFL thickness and LCVA in CC (C) and CT/TT (D) RR-MS patients. * means p

Figure 5. Effect of SNP rs4880213 on…

Figure 5. Effect of SNP rs4880213 on cognitive performances in MS.

A. The graph shows…

Figure 5. Effect of SNP rs4880213 on cognitive performances in MS.
A. The graph shows that the frequency of cognitive preserved (CP) subjects, with at least five years of disease, was higher among RR-MS patients with T allele. B. The CII was lower among RR-MS patients with T allele. C. The graphs show that the frequency of cognitive impaired (CI) subjects was not higher among PP-MS subjects homozygous for T allele. D. The CII was not significantly higher among PP-MS subjects homozygous for T allele. ** means p
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References
    1. Centonze D, Rossi S, Tortiglione A, Picconi B, Prosperetti C, et al. (2007) Synaptic plasticity during recovery from permanent occlusion of the middle cerebral artery. Neurobiol Dis 27: 44–53. - PubMed
    1. Li R, Huang FS, Abbas AK, Wigström H (2007) Role of NMDA receptor subtypes in different forms of NMDA-dependent synaptic plasticity. BMC Neurosci 8: 55. - PMC - PubMed
    1. Yaka R, Biegon A, Grigoriadis N, Simeonidou C, Grigoriadis S, et al. (2007) D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury. FASEB J 21: 2033–2041. - PubMed
    1. Molina-Luna K, Pekanovic A, Röhrich S, Hertler B, Schubring-Giese M, et al. (2009) Dopamine in motor cortex is necessary for skill learning and synaptic plasticity. PLoS One 4: e7082. - PMC - PubMed
    1. Di Lazzaro V, Profice P, Pilato F, Capone F, Ranieri F, et al. (2010) Motor cortex plasticity predicts recovery in acute stroke. Cereb Cortex 20: 1523–1528. - PubMed
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Figure 2. Effect of SNP rs4880213 on…
Figure 2. Effect of SNP rs4880213 on disability progression in MS.
A. The graph shows that PI was lower among RR-MS patients with T allele. B. PI was higher among PP-MS subjects homozygous for T allele. C. Disability progression at MSFC was less frequent among RR-MS patients with T allele. D. The graph shows that early disability progression at MSFC (in the first two years of the disease) was more frequent among PP-MS subjects homozygous for T allele. * means p

Figure 3. Effect of SNP rs4880213 on…

Figure 3. Effect of SNP rs4880213 on clinical and MRI measures of inflammatory activity in…

Figure 3. Effect of SNP rs4880213 on clinical and MRI measures of inflammatory activity in MS.
A. The time to first relapse was lower among RR-MS with CC genotype. B. The time to detect inflammatory activity at MRI was similar between CC and CT/TT RR-MS patients. C. ARR, in the first three years of the disease, was lower among RR-MS patients with T allele. D. The graph shows that T2 lesion volume was similar between CC and CT/TT RR-MS patients. ** means p

Figure 4. Effect of SNP rs4880213 on…

Figure 4. Effect of SNP rs4880213 on functional and morphological indexes of neuronal damage in…

Figure 4. Effect of SNP rs4880213 on functional and morphological indexes of neuronal damage in MS.
A. RNFL thickness was similar between CC and CT/TT RR-MS patients. B. RNFL thickness was lower among PP-MS subjects homozygous for T allele. C, D. Correlation analyses between RNFL thickness and LCVA in CC (C) and CT/TT (D) RR-MS patients. * means p

Figure 5. Effect of SNP rs4880213 on…

Figure 5. Effect of SNP rs4880213 on cognitive performances in MS.

A. The graph shows…

Figure 5. Effect of SNP rs4880213 on cognitive performances in MS.
A. The graph shows that the frequency of cognitive preserved (CP) subjects, with at least five years of disease, was higher among RR-MS patients with T allele. B. The CII was lower among RR-MS patients with T allele. C. The graphs show that the frequency of cognitive impaired (CI) subjects was not higher among PP-MS subjects homozygous for T allele. D. The CII was not significantly higher among PP-MS subjects homozygous for T allele. ** means p
Similar articles
Cited by
References
    1. Centonze D, Rossi S, Tortiglione A, Picconi B, Prosperetti C, et al. (2007) Synaptic plasticity during recovery from permanent occlusion of the middle cerebral artery. Neurobiol Dis 27: 44–53. - PubMed
    1. Li R, Huang FS, Abbas AK, Wigström H (2007) Role of NMDA receptor subtypes in different forms of NMDA-dependent synaptic plasticity. BMC Neurosci 8: 55. - PMC - PubMed
    1. Yaka R, Biegon A, Grigoriadis N, Simeonidou C, Grigoriadis S, et al. (2007) D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury. FASEB J 21: 2033–2041. - PubMed
    1. Molina-Luna K, Pekanovic A, Röhrich S, Hertler B, Schubring-Giese M, et al. (2009) Dopamine in motor cortex is necessary for skill learning and synaptic plasticity. PLoS One 4: e7082. - PMC - PubMed
    1. Di Lazzaro V, Profice P, Pilato F, Capone F, Ranieri F, et al. (2010) Motor cortex plasticity predicts recovery in acute stroke. Cereb Cortex 20: 1523–1528. - PubMed
Show all 111 references
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Follow NCBI
Figure 3. Effect of SNP rs4880213 on…
Figure 3. Effect of SNP rs4880213 on clinical and MRI measures of inflammatory activity in MS.
A. The time to first relapse was lower among RR-MS with CC genotype. B. The time to detect inflammatory activity at MRI was similar between CC and CT/TT RR-MS patients. C. ARR, in the first three years of the disease, was lower among RR-MS patients with T allele. D. The graph shows that T2 lesion volume was similar between CC and CT/TT RR-MS patients. ** means p

Figure 4. Effect of SNP rs4880213 on…

Figure 4. Effect of SNP rs4880213 on functional and morphological indexes of neuronal damage in…

Figure 4. Effect of SNP rs4880213 on functional and morphological indexes of neuronal damage in MS.
A. RNFL thickness was similar between CC and CT/TT RR-MS patients. B. RNFL thickness was lower among PP-MS subjects homozygous for T allele. C, D. Correlation analyses between RNFL thickness and LCVA in CC (C) and CT/TT (D) RR-MS patients. * means p

Figure 5. Effect of SNP rs4880213 on…

Figure 5. Effect of SNP rs4880213 on cognitive performances in MS.

A. The graph shows…

Figure 5. Effect of SNP rs4880213 on cognitive performances in MS.
A. The graph shows that the frequency of cognitive preserved (CP) subjects, with at least five years of disease, was higher among RR-MS patients with T allele. B. The CII was lower among RR-MS patients with T allele. C. The graphs show that the frequency of cognitive impaired (CI) subjects was not higher among PP-MS subjects homozygous for T allele. D. The CII was not significantly higher among PP-MS subjects homozygous for T allele. ** means p
Similar articles
Cited by
References
    1. Centonze D, Rossi S, Tortiglione A, Picconi B, Prosperetti C, et al. (2007) Synaptic plasticity during recovery from permanent occlusion of the middle cerebral artery. Neurobiol Dis 27: 44–53. - PubMed
    1. Li R, Huang FS, Abbas AK, Wigström H (2007) Role of NMDA receptor subtypes in different forms of NMDA-dependent synaptic plasticity. BMC Neurosci 8: 55. - PMC - PubMed
    1. Yaka R, Biegon A, Grigoriadis N, Simeonidou C, Grigoriadis S, et al. (2007) D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury. FASEB J 21: 2033–2041. - PubMed
    1. Molina-Luna K, Pekanovic A, Röhrich S, Hertler B, Schubring-Giese M, et al. (2009) Dopamine in motor cortex is necessary for skill learning and synaptic plasticity. PLoS One 4: e7082. - PMC - PubMed
    1. Di Lazzaro V, Profice P, Pilato F, Capone F, Ranieri F, et al. (2010) Motor cortex plasticity predicts recovery in acute stroke. Cereb Cortex 20: 1523–1528. - PubMed
Show all 111 references
Publication types
MeSH terms
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM

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The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

Follow NCBI
Figure 4. Effect of SNP rs4880213 on…
Figure 4. Effect of SNP rs4880213 on functional and morphological indexes of neuronal damage in MS.
A. RNFL thickness was similar between CC and CT/TT RR-MS patients. B. RNFL thickness was lower among PP-MS subjects homozygous for T allele. C, D. Correlation analyses between RNFL thickness and LCVA in CC (C) and CT/TT (D) RR-MS patients. * means p

Figure 5. Effect of SNP rs4880213 on…

Figure 5. Effect of SNP rs4880213 on cognitive performances in MS.

A. The graph shows…

Figure 5. Effect of SNP rs4880213 on cognitive performances in MS.
A. The graph shows that the frequency of cognitive preserved (CP) subjects, with at least five years of disease, was higher among RR-MS patients with T allele. B. The CII was lower among RR-MS patients with T allele. C. The graphs show that the frequency of cognitive impaired (CI) subjects was not higher among PP-MS subjects homozygous for T allele. D. The CII was not significantly higher among PP-MS subjects homozygous for T allele. ** means p
Similar articles
Cited by
References
    1. Centonze D, Rossi S, Tortiglione A, Picconi B, Prosperetti C, et al. (2007) Synaptic plasticity during recovery from permanent occlusion of the middle cerebral artery. Neurobiol Dis 27: 44–53. - PubMed
    1. Li R, Huang FS, Abbas AK, Wigström H (2007) Role of NMDA receptor subtypes in different forms of NMDA-dependent synaptic plasticity. BMC Neurosci 8: 55. - PMC - PubMed
    1. Yaka R, Biegon A, Grigoriadis N, Simeonidou C, Grigoriadis S, et al. (2007) D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury. FASEB J 21: 2033–2041. - PubMed
    1. Molina-Luna K, Pekanovic A, Röhrich S, Hertler B, Schubring-Giese M, et al. (2009) Dopamine in motor cortex is necessary for skill learning and synaptic plasticity. PLoS One 4: e7082. - PMC - PubMed
    1. Di Lazzaro V, Profice P, Pilato F, Capone F, Ranieri F, et al. (2010) Motor cortex plasticity predicts recovery in acute stroke. Cereb Cortex 20: 1523–1528. - PubMed
Show all 111 references
Publication types
MeSH terms
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 5. Effect of SNP rs4880213 on…
Figure 5. Effect of SNP rs4880213 on cognitive performances in MS.
A. The graph shows that the frequency of cognitive preserved (CP) subjects, with at least five years of disease, was higher among RR-MS patients with T allele. B. The CII was lower among RR-MS patients with T allele. C. The graphs show that the frequency of cognitive impaired (CI) subjects was not higher among PP-MS subjects homozygous for T allele. D. The CII was not significantly higher among PP-MS subjects homozygous for T allele. ** means p

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