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.

Background: Tissue plasminogen activator (tPA) is a serine protease involved in fibrinolysis. It is released by endothelial cells, but also expressed by neurons and glial cells in the central nervous system (CNS). Interestingly, this enzyme also contributes to pathological processes in the CNS such as neuroinflammation by activating microglia and increasing blood–brain barrier permeability. Nevertheless, its role in the control of adaptive and innate immune response remains poorly understood.Methods: tPA effects on myeloid and lymphoid cell response were studiedin vivoin the mouse model of multiple sclerosis experimental autoimmune encephalomyelitis andin vitroin splenocytes.Results: tPA^-/-animals exhibited less severe experimental autoimmune encephalomyelitis than their wild-type counterparts. This was accompanied by a reduction in both lymphoid and myeloid cell populations in the spinal cord parenchyma. In parallel, tPA increased T cell activation and proliferation, as well as cytokine production by a protease-dependent mechanism andviaplasmin generation. In addition, tPA directly raised the expression of MHC-II and the co-stimulatory molecules CD80 and CD86 at the surface of dendritic cells and macrophages by a direct action dependent of the activation of epidermal growth factor receptor.Conclusions: Our study provides new insights into the mechanisms responsible for the harmful functions of tPA in multiple sclerosis and its animal models: tPA promotes the proliferation and activation of both lymphoid and myeloid populations by distinct, though complementary, mechanisms.

Previous studies showed that monoclonal immunoglobulins G (IgGs) of “monoclonal gammopathy of undetermined significance” (MGUS) and myeloma were hyposialylated, thus presumably pro-inflammatory, and for about half of patients, the target of the monoclonal IgG was either a virus—Epstein–Barr virus (EBV), other herpes viruses, hepatitis C virus (HCV)—or a glucolipid, lysoglucosylceramide (LGL1), suggesting antigen-driven disease in these patients. In the present study, we show that monoclonal IgAs share these characteristics. We collected 35 sera of patients with a monoclonal IgA (6 MGUS, 29 myeloma), and we were able to purify 25 of the 35 monoclonal IgAs (6 MGUS, 19 myeloma). Monoclonal IgAs from MGUS and myeloma patients were significantly less sialylated than IgAs from healthy volunteers. When purified monoclonal IgAs were tested against infectious pathogens and LGL1, five myeloma patients had a monoclonal IgA that specifically recognized viral proteins: the core protein of HCV in one case, EBV nuclear antigen 1 (EBNA-1) in four cases (21.1% of IgA myeloma). Monoclonal IgAs from three myeloma patients reacted against LGL1. In summary, monoclonal IgAs are hyposialylated and as described for IgG myeloma, significant subsets (8/19, or 42%) of patients with IgA myeloma may have viral or self (LGL1) antigen-driven disease.

Background: Anti-N-Methyl-d-aspartate receptor (NMDAR) autoimmune encephalitis (NMDAR AE) is an autoimmune disease characterized by severe psychiatric and neurological symptoms. While the pathogenic role of antibodies (Abs) directed against the GluN1 subunit of NMDAR is well described in this disease, the immune mechanisms involved in the generation of the autoimmune B cell response, especially the role of T helper cells, are poorly understood. Previously, we developed a B-cell-mediated mouse model of NMDAR AE by immunization with a GluN1_359–378 peptide that drives a series of symptoms that recapitulate AE such as anxiety behaviour and spatial memory impairment. Results: In this mouse model, we identified anti-GluN1-specific CD4⁺ but also CD8⁺ T cells in both spleen and meninges. T helper cells have a polyfunctional profile, arguing for a T and B cell crosstalk to generate anti-GluN1 pathogenic Abs. Interestingly, proteomic analysis of AE meninges showed enrichment of differentially expressed proteins in biological processes associated with B cell activation and cytokine signalling pathways. Conclusions: This study identified, for the first time, a potential contribution of T helper cells in the pathology of NMDAR AE and paved the way for the development of future tolerogenic approaches to treat relapses.

Background: General anesthesia is administered to millions of children annually, yet its long-term effects on neurodevelopment remain a concern. It was previously reported that even a single early exposure to general anesthesia for minor surgery impairs visual attention in children. This study investigates the effects of early repeated general anesthesia exposure on visual system maturation in mice and explores the role of tissue-type plasminogen activator in mediating these effects during development. Methods: Male SWISS and C57BL/6J mice (wild-type or deficient for tissue-type plasminogen activator) were exposed to general anesthesia with 1.3% isoflurane in 50% oxygen for 90 min per day from postnatal days 4 to 10. Control animals received 50% oxygen alone. Visual system integrity and inflammation were assessed at postnatal day 15 and at 6 weeks using behavioral tests, high-resolution imaging, and immunohistochemistry. In SWISS mice, circulating tissue-type plasminogen activator levels were measured using a biochemical approach, and neurovascular coupling was evaluated by functional ultrasound imaging. Results: Early repeated general anesthesia exposure delayed eyelid opening (median postnatal day 13 [95% CI, 0.52 to 1.45] vs. postnatal day 15 [95% CI, 0.62 to 1.92]; P < 0.0001), caused lasting visual function deficits (depth perception and oculomotor reflex), and reduced retinal (0.2627 ± 0.04 mm vs. 0.1667 ± 0.03 mm; P < 0.0001) and primary visual cortex thickness (0.8000 ± 0.08 mm vs. 0.7282 ± 0.05 mm; P = 0.0235). Notably, lower circulating tissue-type plasminogen activator levels were observed in general anesthesia–exposed SWISS mice (11.580 ± 2.19 ng/ml vs. 7.654 ± 1.31 ng/ml; P = 0.0082). Tissue-type plasminogen activator–deficient mice exhibited attenuated or absent general anesthesia–induced visual alterations. Conclusions: These findings indicate that early repeated exposure to general anesthesia disrupts visual system maturation in mice and suggest that altered tissue-type plasminogen activator pathways may contribute to these effects, identifying tissue-type plasminogen activator as a potential marker of anesthesia-related neurodevelopmental vulnerability. Additional experimental work will be required to further support this association and clarify its underlying mechanisms.