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.

A mouse model of seizures in anti–N‐methyl‐d‐aspartate receptor encephalitis

“…14 Although overall clinical improvement in nonparaneoplastic anti-NMDAR encephalitis occurs in <50% of patients following first-line immunotherapy, 15 seizures appear to respond well to conventional anticonvulsants in the majority of patients. 17 The reason for the unsuccessful attempts to reveal spontaneous seizures could be a short duration of treatment with antibodies, 17,18 or that the seizures might have been exclusively electrographic and present without behavioral correlates. 16 Infusion of anti-NMDAR antibodies in mice did not cause seizures unless their seizure threshold had been reduced by the chemical convulsant, pentylenetetrazol.…”

Dopamine-2 receptor extracellular N-terminus regulates receptor surface availability and is the target of human pathogenic antibodies from children with movement and psychiatric disorders

“…To support anti-D2R antibody pathogenicity, patients show improvements after treatment with immunotherapies [13]. Animal transfer experiments could validate human anti-D2R antibody pathogenicity, as demonstrated for anti-AQP4 antibody in neuromyelitis optica [30] and anti-NMDAR antibody in encephalitis [45, 54]. However, the difference in epitope binding between human and mouse D2R could influence the relevance of results obtained in animal studies.…”

Neuroinflammation: Ways in Which the Immune System Affects the Brain

“…A recent animal model using intraventricular infusion of pooled patients' CSF for 14 days resulted in progressive decrease in novel object recognition memory with depressed behavior, correlating over time with decrease of hippocampal NMDAR [65]. A single intraventricular injection of purified NMDAR IgG into mice increased seizures following the proconvulsant pentylenetetrazol and the number of seizures correlated with the antibodies bound to the hippocampus [66].…”