Epileptogenic effects of NMDAR antibodies in a passive transfer mouse model

Sukhvir Wright, Kevan Hashemi, Lukasz Stasiak, Julian Bartram, Bethan Lang, Angela Vincent*, A. Louise Upton

*Corresponding author for this work

Research output: Contribution to journalArticle

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 (R2 = 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.

Original languageEnglish
Pages (from-to)3159-3167
Number of pages9
JournalBrain research
Volume138
Issue number11
Early online date15 Sep 2015
DOIs
Publication statusPublished - 1 Nov 2015

Bibliographical note

This is a pre-copyedited, author-produced PDF of an article accepted for publication in Brain following peer review. The version of record Sukhvir Wright, Kevan Hashemi, Lukasz Stasiak, Julian Bartram, Bethan Lang, Angela Vincent, A. Louise Upton; Epileptogenic effects of NMDAR antibodies in a passive transfer mouse model, Brain, Volume 138, Issue 11, 1 November 2015, Pages 3159–3167 is available online at: https://doi.org/10.1093/brain/awv257

Keywords

  • antibody
  • mouse electroencephalography
  • NMDAR
  • seizures

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