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NMDA Receptors in Health and Diseases: New Roles and Signaling Pathways—Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Autoantibodies as Potential Biomarkers of Fatigue in Patients with Rheumatic Diseases

by Tatjana Marinoska, Tamara Möckel, Konstantinos Triantafyllias, Sebastian Boegel, Matthias Dreher, Felix Luessi and Andreas Schwarting

Int. J. Mol. Sci. 2023, 24(4), 3560; https://doi.org/10.3390/ijms24043560 - 10 Feb 2023

Cited by 1 | Viewed by 1524

Abstract

Fatigue is a widespread and complex symptom with motor and cognitive components; it is diagnosed predominantly by questionnaire. We recently published a correlation between anti-N-methyl-D-aspartate receptor (NMDAR) antibodies and fatigue in patients with SLE (systemic lupus erythematosus). In the present study, we examined [...] Read more.

Fatigue is a widespread and complex symptom with motor and cognitive components; it is diagnosed predominantly by questionnaire. We recently published a correlation between anti-N-methyl-D-aspartate receptor (NMDAR) antibodies and fatigue in patients with SLE (systemic lupus erythematosus). In the present study, we examined whether this association also applies to patients with other rheumatic diseases. Serum samples of 88 patients with different rheumatic diseases were analyzed for the presence of anti-NR2 antibodies and Neurofilament light chain (NfL) protein. The severity of fatigue was determined according to the FSMC questionnaire (Fatigue Scale for Motor and Cognitive Functions) and correlated with the circulating antibody titer and NfL level accordingly. Positive titers of anti-NR2 antibodies were detected in patients with both autoimmune and non-autoimmune rheumatic diseases. These patients suffer predominantly from severe fatigue. The circulating NfL level did not correlate with the anti-NR2 titer and the fatigue severity in all patient groups. The association of severe fatigue with circulating anti-NR2 antibodies in patients with rheumatic diseases, independently from the main disease, suggests an individual role of these autoantibodies in fatigue pathophysiology. Thus, the detection of these autoantibodies might be a helpful diagnostic tool in rheumatic patients with fatigue. Full article

(This article belongs to the Special Issue NMDA Receptors in Health and Diseases: New Roles and Signaling Pathways)

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17 pages, 2664 KiB

Open AccessArticle

Impact of Mephedrone on Fear Memory in Adolescent Rats: Involvement of Matrix Metalloproteinase-9 (MMP-9) and N-Methyl-D-aspartate (NMDA) Receptor

by Pawel Grochecki, Irena Smaga, Karolina Wydra, Marta Marszalek-Grabska, Tymoteusz Slowik, Ewa Kedzierska, Joanna Listos, Ewa Gibula-Tarlowska, Malgorzata Filip and Jolanta H. Kotlinska

Int. J. Mol. Sci. 2023, 24(3), 1941; https://doi.org/10.3390/ijms24031941 - 18 Jan 2023

Cited by 3 | Viewed by 1883

Abstract

Treatment of Post-Traumatic Stress Disorder (PTSD) is complicated by the presence of drug use disorder comorbidity. Here, we examine whether conditioned fear (PTSD model) modifies the rewarding effect of mephedrone and if repeated mephedrone injections have impact on trauma-related behaviors (fear sensitization, extinction, [...] Read more.

Treatment of Post-Traumatic Stress Disorder (PTSD) is complicated by the presence of drug use disorder comorbidity. Here, we examine whether conditioned fear (PTSD model) modifies the rewarding effect of mephedrone and if repeated mephedrone injections have impact on trauma-related behaviors (fear sensitization, extinction, and recall of the fear reaction). We also analyzed whether these trauma-induced changes were associated with exacerbation in metalloproteinase-9 (MMP-9) and the GluN2A and GluN2B subunits of N-methyl-D-aspartate (NMDA) glutamate receptor expression in such brain structures as the hippocampus and basolateral amygdala. Male adolescent rats underwent trauma exposure (1.5 mA footshock), followed 7 days later by a conditioned place preference training with mephedrone. Next, the post-conditioning test was performed. Fear sensitization, conditioned fear, anxiety-like behavior, extinction acquisition and relapse were then assessed to evaluate behavioral changes. MMP-9, GluN2A and GluN2B were subsequently measured. Trauma-exposed rats subjected to mephedrone treatment acquired a strong place preference and exhibited impairment in fear extinction and reinstatement. Mephedrone had no effect on trauma-induced MMP-9 level in the basolateral amygdala, but decreased it in the hippocampus. GluN2B expression was decreased in the hippocampus, but increased in the basolateral amygdala of mephedrone-treated stressed rats. These data suggest that the modification of the hippocampus and basolateral amygdala due to mephedrone use can induce fear memory impairment and drug seeking behavior in adolescent male rats. Full article

(This article belongs to the Special Issue NMDA Receptors in Health and Diseases: New Roles and Signaling Pathways)

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15 pages, 2725 KiB

Open AccessArticle

Improved NMDA Receptor Activation by the Secreted Amyloid-Protein Precursor-α in Healthy Aging: A Role for D-Serine?

by Jean-Marie Billard and Thomas Freret

Int. J. Mol. Sci. 2022, 23(24), 15542; https://doi.org/10.3390/ijms232415542 - 8 Dec 2022

Cited by 2 | Viewed by 1638

Abstract

Impaired activation of the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) by D-serine is linked to cognitive aging. Whether this deregulation may be used to initiate pharmacological strategies has yet to be considered. To this end, we performed electrophysiological extracellular recordings at CA3/CA1 synapses [...] Read more.

Impaired activation of the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) by D-serine is linked to cognitive aging. Whether this deregulation may be used to initiate pharmacological strategies has yet to be considered. To this end, we performed electrophysiological extracellular recordings at CA3/CA1 synapses in hippocampal slices from young and aged mice. We show that 0.1 nM of the soluble N-terminal recombinant fragment of the secreted amyloid-protein precursor-α (sAPPα) added in the bath significantly increased NMDAR activation in aged but not adult mice without impacting basal synaptic transmission. In addition, sAPPα rescued the age-related deficit of theta-burst-induced long-term potentiation. Significant NMDAR improvement occurred in adult mice when sAPPα was raised to 1 nM, and this effect was drastically reduced in transgenic mice deprived of D-serine through genetic deletion of the synthesizing enzyme serine racemase. Altogether, these results emphasize the interest to consider sAPPα treatment targeting D-serine-dependent NMDAR deregulation to alleviate cognitive aging. Full article

(This article belongs to the Special Issue NMDA Receptors in Health and Diseases: New Roles and Signaling Pathways)

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17 pages, 2088 KiB

Open AccessArticle

NX210c Peptide Promotes Glutamatergic Receptor-Mediated Synaptic Transmission and Signaling in the Mouse Central Nervous System

by Sighild Lemarchant, Mélissa Sourioux, Juliette Le Douce, Alexandre Henriques, Noëlle Callizot, Sandrine Hugues, Mélissa Farinelli and Yann Godfrin

Int. J. Mol. Sci. 2022, 23(16), 8867; https://doi.org/10.3390/ijms23168867 - 9 Aug 2022

Cited by 1 | Viewed by 2326

Abstract

NX210c is a disease-modifying dodecapeptide derived from the subcommissural organ-spondin that is under preclinical and clinical development for the treatment of neurological disorders. Here, using whole-cell patch-clamp recordings, we demonstrate that NX210c increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and GluN2A-containing N-methyl-D-aspartate receptor (GluN2A-NMDAR)-mediated excitatory [...] Read more.

NX210c is a disease-modifying dodecapeptide derived from the subcommissural organ-spondin that is under preclinical and clinical development for the treatment of neurological disorders. Here, using whole-cell patch-clamp recordings, we demonstrate that NX210c increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and GluN2A-containing N-methyl-D-aspartate receptor (GluN2A-NMDAR)-mediated excitatory postsynaptic currents in the brain. Accordingly, using extracellular field excitatory postsynaptic potential recordings, an enhancement of synaptic transmission was shown in the presence of NX210c in two different neuronal circuits. Furthermore, the modulation of synaptic transmission and GluN2A-NMDAR-driven signaling by NX210c restored memory in mice chronically treated with the NMDAR antagonist phencyclidine. Overall, by promoting glutamatergic receptor-related neurotransmission and signaling, NX210c represents an innovative therapeutic opportunity for patients suffering from CNS disorders, injuries, and states with crippling synaptic dysfunctions. Full article

(This article belongs to the Special Issue NMDA Receptors in Health and Diseases: New Roles and Signaling Pathways)

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21 pages, 2227 KiB

Open AccessArticle

Maternal Separation Alters Ethanol Drinking and Reversal Learning Processes in Adolescent Rats: The Impact of Sex and Glycine Transporter Type 1 (GlyT1) Inhibitor

by Joanna Filarowska-Jurko, Lukasz Komsta, Irena Smaga, Paulina Surowka, Marta Marszalek-Grabska, Pawel Grochecki, Dorota Nizio, Malgorzata Filip and Jolanta H. Kotlinska

Int. J. Mol. Sci. 2022, 23(10), 5350; https://doi.org/10.3390/ijms23105350 - 11 May 2022

Cited by 8 | Viewed by 2212

Abstract

Adverse early life experiences are associated with an enhanced risk for mental and physical health problems, including substance abuse. Despite clinical evidence, the mechanisms underlying these relationships are not fully understood. Maternal separation (MS) is a commonly used animal model of early neglect. [...] Read more.

Adverse early life experiences are associated with an enhanced risk for mental and physical health problems, including substance abuse. Despite clinical evidence, the mechanisms underlying these relationships are not fully understood. Maternal separation (MS) is a commonly used animal model of early neglect. The aim of the current study is to determine whether the N-methyl-D-aspartate receptor (NMDAR)/glycine sites are involved in vulnerability to alcohol consumption (two-bottle choice paradigm) and reversal learning deficits (Barnes maze task) in adolescent rats subjected to the MS procedure and whether these effects are sex dependent. By using ELISA, we evaluated MS-induced changes in the NMDAR subunits (GluN1, GluN2A, GluN2B) expression, especially in the glycine-binding subunit, GluN1, in the prefrontal cortex (PFC) and ventral striatum (vSTR) of male/female rats. Next, we investigated whether Org 24598, a glycine transporter 1 (GlyT1) inhibitor, was able to modify ethanol drinking in adolescent and adult male/female rats with prior MS experience and reversal learning in the Barnes maze task. Our findings revealed that adolescent MS female rats consumed more alcohol which may be associated with a substantial increase in GluN1 subunit of NMDAR in the PFC and vSTR. Org 24598 decreased ethanol intake in both sexes with a more pronounced decrease in ethanol consumption in adolescent female rats. Furthermore, MS showed deficits in reversal learning in both sexes. Org 24598 ameliorated reversal learning deficits, and this effect was reversed by the NMDAR/glycine site inhibitor, L-701,324. Collectively, our results suggest that NMDAR/glycine sites might be targeted in the treatment of alcohol abuse in adolescents with early MS, especially females. Full article

(This article belongs to the Special Issue NMDA Receptors in Health and Diseases: New Roles and Signaling Pathways)

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20 pages, 7390 KiB

Open AccessArticle

Two-Chains Tissue Plasminogen Activator Unifies Met and NMDA Receptor Signalling to Control Neuronal Survival

by Elodie Hedou, Sara Douceau, Arnaud Chevilley, Alexandre Varangot, Audrey M. Thiebaut, Hortense Triniac, Isabelle Bardou, Carine Ali, Mike Maillasson, Tiziana Crepaldi, Paolo Comoglio, Eloïse Lemarchand, Véronique Agin, Benoit D. Roussel and Denis Vivien

Int. J. Mol. Sci. 2021, 22(24), 13483; https://doi.org/10.3390/ijms222413483 - 15 Dec 2021

Cited by 10 | Viewed by 2485

Abstract

Tissue-type plasminogen activator (tPA) plays roles in the development and the plasticity of the nervous system. Here, we demonstrate in neurons, that by opposition to the single chain form (sc-tPA), the two-chains form of tPA (tc-tPA) activates the MET receptor, leading to the [...] Read more.

Tissue-type plasminogen activator (tPA) plays roles in the development and the plasticity of the nervous system. Here, we demonstrate in neurons, that by opposition to the single chain form (sc-tPA), the two-chains form of tPA (tc-tPA) activates the MET receptor, leading to the recruitment of N-Methyl-d-Aspartate receptors (NMDARs) and to the endocytosis and proteasome-dependent degradation of NMDARs containing the GluN2B subunit. Accordingly, tc-tPA down-regulated GluN2B-NMDAR-driven signalling, a process prevented by blockers of HGFR/MET and mimicked by its agonists, leading to a modulation of neuronal death. Thus, our present study unmasks a new mechanism of action of tPA, with its two-chains form mediating a crosstalk between MET and the GluN2B subunit of NMDARs to control neuronal survival. Full article

(This article belongs to the Special Issue NMDA Receptors in Health and Diseases: New Roles and Signaling Pathways)

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Review

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20 pages, 1782 KiB

Open AccessReview

NMDA Receptor C-Terminal Domain Signalling in Development, Maturity, and Disease

by Kirsty Haddow, Peter C. Kind and Giles E. Hardingham

Int. J. Mol. Sci. 2022, 23(19), 11392; https://doi.org/10.3390/ijms231911392 - 27 Sep 2022

Cited by 9 | Viewed by 2814

Abstract

The NMDA receptor is a Ca²⁺-permeant glutamate receptor which plays key roles in health and disease. Canonical NMDARs contain two GluN2 subunits, of which 2A and 2B are predominant in the forebrain. Moreover, the relative contribution of 2A vs. 2B is [...] Read more.

The NMDA receptor is a Ca²⁺-permeant glutamate receptor which plays key roles in health and disease. Canonical NMDARs contain two GluN2 subunits, of which 2A and 2B are predominant in the forebrain. Moreover, the relative contribution of 2A vs. 2B is controlled both developmentally and in an activity-dependent manner. The GluN2 subtype influences the biophysical properties of the receptor through difference in their N-terminal extracellular domain and transmembrane regions, but they also have large cytoplasmic Carboxyl (C)-terminal domains (CTDs) which have diverged substantially during evolution. While the CTD identity does not influence NMDAR subunit specific channel properties, it determines the nature of CTD-associated signalling molecules and has been implicated in mediating the control of subunit composition (2A vs. 2B) at the synapse. Historically, much of the research into the differential function of GluN2 CTDs has been conducted in vitro by over-expressing mutant subunits, but more recently, the generation of knock-in (KI) mouse models have allowed CTD function to be probed in vivo and in ex vivo systems without heterologous expression of GluN2 mutants. In some instances, findings involving KI mice have been in disagreement with models that were proposed based on earlier approaches. This review will examine the current research with the aim of addressing these controversies and how methodology may contribute to differences between studies. We will also discuss the outstanding questions regarding the role of GluN2 CTD sequences in regulating NMDAR subunit composition, as well as their relevance to neurodegenerative disease and neurodevelopmental disorders. Full article

(This article belongs to the Special Issue NMDA Receptors in Health and Diseases: New Roles and Signaling Pathways)

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39 pages, 1288 KiB

Open AccessReview

Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

by Célia Seillier, Flavie Lesept, Olivier Toutirais, Fanny Potzeha, Manuel Blanc and Denis Vivien

Int. J. Mol. Sci. 2022, 23(18), 10336; https://doi.org/10.3390/ijms231810336 - 7 Sep 2022

Cited by 17 | Viewed by 7596

Abstract

The excitatory neurotransmission of the central nervous system (CNS) mainly involves glutamate and its receptors, especially N-methyl-D-Aspartate receptors (NMDARs). These receptors have been extensively described on neurons and, more recently, also on other cell types. Nowadays, the study of their differential expression and [...] Read more.

The excitatory neurotransmission of the central nervous system (CNS) mainly involves glutamate and its receptors, especially N-methyl-D-Aspartate receptors (NMDARs). These receptors have been extensively described on neurons and, more recently, also on other cell types. Nowadays, the study of their differential expression and function is taking a growing place in preclinical and clinical research. The diversity of NMDAR subtypes and their signaling pathways give rise to pleiotropic functions such as brain development, neuronal plasticity, maturation along with excitotoxicity, blood-brain barrier integrity, and inflammation. NMDARs have thus emerged as key targets for the treatment of neurological disorders. By their large extracellular regions and complex intracellular structures, NMDARs are modulated by a variety of endogenous and pharmacological compounds. Here, we will present an overview of NMDAR functions on neurons and other important cell types involved in the pathophysiology of neurodegenerative, neurovascular, mental, autoimmune, and neurodevelopmental diseases. We will then discuss past and future development of NMDAR targeting drugs, including innovative and promising new approaches. Full article

(This article belongs to the Special Issue NMDA Receptors in Health and Diseases: New Roles and Signaling Pathways)

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