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.
Highlights
Glutamate is the main excitatory neurotransmitter in the mammalian brain, responsible for basal excitatory synaptic transmission and for many forms of synaptic plasticity
As we have already done in healthy individuals [17], we explored in a subgroup of multiple sclerosis (MS) patients (n = 84, 56 female, age 3969 years, Expanded Disability Status Scale (EDSS): 2.661.2) the impact of allelic variants of the four NMDA receptors (NMDARs) single nucleotide polymorphisms (SNPs) in cortical excitability explored through paired TMS experiments
Candidate gene studies with hypotheses driven by prior research remain a valuable approach for the definition of the role played by specific molecules and pathways in a given disease
Summary
Glutamate is the main excitatory neurotransmitter in the mammalian brain, responsible for basal excitatory synaptic transmission and for many forms of synaptic plasticity. The stimulation of glutamate NMDA receptors (NMDARs) has the potential of limiting the clinical manifestations of neuronal damage by promoting compensatory plasticity in surviving neurons [1,2,3,4,5], but sustained activation of these receptors can be per se neurotoxic [6,7,8,9,10,11]. In relapsing-remitting MS (RRMS), a certain degree of inflammatory white matter damage is generally well tolerated, and reversible or irreversible clinical disability only appears when the adaptive abilities of the brain fail. Whether NMDARs are directly involved in MS pathophysiology is unknown
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