title: Epileptogenic effects of NMDAR antibodies in a passive transfer mouse model.
abstract: Most patients with N-methyl D-aspartate-receptor antibody encephalitis develop seizures but the epileptogenicity of the antibodies has not been investigated in vivo. Wireless electroencephalogram transmitters were implanted into 23 C57BL/6 mice before left lateral ventricle injection of antibody-positive (test) or healthy (control) immunoglobulin G. Mice were challenged 48 h later with a subthreshold dose (40 mg/kg) of the chemo-convulsant pentylenetetrazol and events recorded over 1 h. Seizures were assessed by video observation of each animal and the electroencephalogram by an automated seizure detection programme. No spontaneous seizures were seen with the antibody injections. However, after the pro-convulsant, the test mice (n = 9) had increased numbers of observed convulsive seizures (P = 0.004), a higher total seizure score (P = 0.003), and a higher number of epileptic 'spike' events (P = 0.023) than the control mice (n = 6). At post-mortem, surprisingly, the total number of N-methyl D-aspartate receptors did not differ between test and control mice, but in test mice the levels of immunoglobulin G bound to the left hippocampus were higher (P < 0.0001) and the level of bound immunoglobulin G correlated with the seizure scores (R(2) = 0.8, P = 0.04, n = 5). Our findings demonstrate the epileptogenicity of N-methyl D-aspartate receptor antibodies in vivo, and suggest that binding of immunoglobulin G either reduced synaptic localization of N-methyl D-aspartate receptors, or had a direct effect on receptor function, which could be responsible for seizure susceptibility in this acute short-term model.
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
authors.forename: Sukhvir
authors.initials: S
authors.lastname: Wright
authors.affiliation: 2 Open Source Instruments Inc, 130 Mount Auburn Street, Watertown, MA 02472, USA.
authors.forename: Kevan
authors.initials: K
authors.lastname: Hashemi
authors.affiliation: 3 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Stasiak
authors.affiliation: 3 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Bartram
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
authors.forename: Bethan
authors.initials: B
authors.lastname: Lang
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK angela.vincent@ndcn.ox.ac.uk.
authors.forename: Angela
authors.initials: A
authors.lastname: Vincent
authors.affiliation: 3 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK angela.vincent@ndcn.ox.ac.uk.
authors.forename: A Louise
authors.initials: AL
authors.lastname: Upton
mesh_terms: D000818:Animals; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis / Q000150:complications / Q000276:immunology* / Q000503:physiopathology; D001323:Autoantibodies / Q000276:immunology*; D001921:Brain / Q000276:immunology / Q000378:metabolism; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004569:Electroencephalography; D005260:Female; D006624:Hippocampus / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G; D051379:Mice; D008810:Mice, Inbred C57BL; D010433:Pentylenetetrazole / Q000633:toxicity; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology* / Q000378:metabolism; D012640:Seizures / Q000209:etiology / Q000276:immunology* / Q000503:physiopathology
chemical_list: D001323:Autoantibodies; D003292:Convulsants; D007074:Immunoglobulin G; D016194:Receptors, N-Methyl-D-Aspartate; D010433:Pentylenetetrazole
keywords: NMDAR; antibody; mouse electroencephalography; seizures