Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. Brain

CNRS, Interdisciplinary Institute for Neurosciences UMR 5297, Universite de Bordeaux, 146 rue Leo Saignat, Bordeaux, France.
Brain (Impact Factor: 9.2). 05/2012; 135(Pt 5):1606-21. DOI: 10.1093/brain/aws092
Source: PubMed


Autoimmune synaptic encephalitides are recently described human brain diseases leading to psychiatric and neurological syndromes through inappropriate brain-autoantibody interactions. The most frequent synaptic autoimmune encephalitis is associated with autoantibodies against extracellular domains of the glutamatergic N-methyl-d-aspartate receptor, with patients developing psychotic and neurological symptoms in an autoantibody titre-dependent manner. Although N-methyl-d-aspartate receptors are the primary target of these antibodies, the cellular and molecular pathway(s) that rapidly lead to N-methyl-d-aspartate receptor dysfunction remain poorly understood. In this report, we used a unique combination of high-resolution nanoparticle and bulk live imaging approaches to demonstrate that anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis strongly alter, in a time-dependent manner, the surface content and trafficking of GluN2-NMDA receptor subtypes. Autoantibodies laterally displaced surface GluN2A-NMDA receptors out of synapses and completely blocked synaptic plasticity. This loss of extrasynaptic and synaptic N-methyl-d-aspartate receptor is prevented both in vitro and in vivo, by the activation of EPHB2 receptors. Indeed, the anti-N-methyl-d-aspartate receptor autoantibodies weaken the interaction between the extracellular domains of the N-methyl-d-aspartate and Ephrin-B2 receptors. Together, we demonstrate that the anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis alter the dynamic retention of synaptic N-methyl-d-aspartate receptor through extracellular domain-dependent mechanism(s), shedding new light on the pathology of the neurological and psychiatric disorders observed in these patients and opening possible new therapeutic strategies.

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    • "Therefore, it might be difficult to stain bovine ovaries and ova using an anti-NR2A antibody (clone A12W, Upstate, Lake Placid, NY). NMDAR is a membrane-associated protein that is usually localized at the synapse as well as the extrasynaptic receptor (Gleichman et al. 2012; Mikasova et al. 2012). Although the NMDAR that was isolated from the bovine ovum cell membrane in this study is classified as extrasynaptic , we have shown that IgG purified from the serum of a patient with anti-NMDAR encephalitis, which was previ- Fig. 5. Immunocytochemical analysis of the affinity of IgG to the cell membrane of a bovine ovum. "
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    ABSTRACT: Autoimmune synaptic encephalitis is characterized by the presence of autoantibodies against synaptic constituent receptors and manifests as neurological and psychiatric disorders. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is such an autoimmune disorder that predominantly affects young women. It is associated with antibodies against the extracellular region of the NR1 subunit of postsynaptic NMDAR. Each NMDAR functions as a heterotetrameric complex that is composed of four subunits, including NR1 and NR2A, NR2B, or NR2C. Importantly, ovarian teratoma is a typical complication of anti-NMDAR encephalitis in female patients and may contain antigenic neural tissue; however, antigenic sites remain unknown in female patients without ovarian teratoma. The purpose of this study was to investigate the expression of NMDARs in the ovum. We detected NR1 and NR2B immunoreactivity in protein fractions extracted from the bovine ovary and ova by SDS-polyacrylamide gel electrophoresis and immunoblotting analysis. Immunoprecipitates digested with trypsin were analyzed by reverse phase liquid chromatography coupled to tandem mass spectrometry. We obtained the following five peptides: SPFGRFK and KNLQDR, which are consistent with partial sequences of human NR1, and GVEDALVSLK, QPTVAGAPK, and NEVMSSK, which correspond to those of NR2A, NR2B and NR2C, respectively. Immunocytochemical analysis revealed that the bovine ovum was stained with the immunoglobulin G purified from the serum of a patient with anti-NMDAR encephalitis. Taken together, we propose that the normal ovum expresses NMDARs that have strong affinity for the disease-specific IgG. The presence of NMDARs in ova may help explain why young females without ovarian teratomas are also affected by anti-NMDAR encephalitis.
    The Tohoku Journal of Experimental Medicine 03/2015; 235(3):223-31. DOI:10.1620/tjem.235.223 · 1.35 Impact Factor
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    • "They bind to the NR1 subunit of the NMDA-R and disrupt surface cross-talk between NMDA and Ephrin-B2 receptors. This results in the displacement of surface GluN2A-NMDA receptors out of synapses, and leads to a selective and reversible decrease in NMDA-R surface density at the post-synaptic level of the glutamatergic synapse which correlates with antibody titers [6,7]. Inactivation of inhibitory GABAergic interneurons, which express high concentrations of NMDA-R, has also a key role in pathophysiology [1]. "
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    ABSTRACT: Many anesthetic drugs interact with the NMDA receptor and may therefore alter the clinical presentation of anti-NMDA-R encephalitis. A 24-year-old woman was admitted to hospital for decreased consciousness and hyperthermia. Cerebrospinal fluid analysis revealed lymphocytic pleocytosis, and elevated protein. Cultures were negative. Patient state worsened with agitation, facial dyskinesia, ocular deviation, and limb dystonia. Diagnosis of anti-NMDA-R encephalitis was evidenced by specific antibodies. High doses of methylprednisolone were administered. CT scan disclosed an ovarian teratoma and tumor resection was scheduled under anesthesia with propofol, sufentanil, atracurium and sevoflurane. Sedation after surgery was maintained with propofol. Rapidly after surgery, patient's condition deteriorated with increase of dyskinesias, and two tonic-clonic generalized seizure events. In patients with anti-NMDA-R encephalitis, anesthesia using benzodiazepines, opiates and curares, which fail to interfere with the NMDA pathway, should be preferred.
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    • "Encephalitis with anti-N-methyl-D-aspartate receptor antibodies (anti-NMDAR-Ab) is a rapid-onset encephalitis including psychosis, seizures, various movement disorders and autonomic system disturbances. The physiopathology is based on immune-mediated neuronal dysfunction [1,2]. We report the case of a 65-year-old woman presenting an extensive myelitis associated with anti-NMDAR-Ab. "
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    ABSTRACT: Encephalitis with anti-N-methyl-D-aspartate receptor antibodies (anti-NMDAR-Ab) is a rapid-onset encephalitis including psychosis, seizures, various movement disorders and autonomic system disturbances. We report a very unusual case of extensive myelitis associated with anti-NMDAR-Ab. MRI also revealed a hyperintense T2 lesion, non-suggestive of MS, which progressively extended, associated with periventricular gadolinium enhancement visualized on brain MRI. Ophthalmological evaluation showed subclinical right optic neuritis. The absence of anti-AQP4 antibody argued against neuromyelitis optica spectrum disorder. A slight psychomotor slowing prompted us to search for various causes of autoimmune encephalitis. Anti-NMDAR-Ab was found in cerebrospinal fluid. In patients with extensive myelitis who are seronegative for anti-AQP4 antibodies, and after other classical causes have been excluded, the hypothesis of atypical anti-NMDAR-Ab encephalitis should also be considered.
    BMC Neurology 12/2013; 13(1):211. DOI:10.1186/1471-2377-13-211 · 2.04 Impact Factor
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