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

Olga Taraschenko, Howard S. Fox, Sean J. Pittock, Anastasia Zekeridou, Maftuna Gafurova, Ember Eldridge, Jinxu Liu, Shashank M. Dravid, Raymond Dingledine

Research output: Contribution to journalArticle

Abstract

Objective: Seizures develop in 80% of patients with anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality. Anti-NMDAR antibodies have been linked to memory loss in encephalitis; however, their role in seizures has not been established. We determined whether anti-NMDAR antibodies from autoimmune encephalitis patients are pathogenic for seizures. Methods: We performed continuous intracerebroventricular infusion of cerebrospinal fluid (CSF) or purified immunoglobulin (IgG) from the CSF of patients with anti-NMDAR encephalitis or polyclonal rabbit anti-NMDAR IgG, in male C57BL/6 mice. Seizure status during a 2-week treatment was assessed with video-electroencephalography. We assessed memory, anxiety-related behavior, and motor function at the end of treatment and assessed the extent of neuronal damage and gliosis in the CA1 region of hippocampus. We also performed whole-cell patch recordings from the CA1 pyramidal neurons in hippocampal slices of mice with seizures. Results: Prolonged exposure to rabbit anti-NMDAR IgG, patient CSF, or human IgG purified from the CSF of patients with encephalitis induced seizures in 33 of 36 mice. The median number of seizures recorded in 2 weeks was 13, 39, and 35 per mouse in these groups, respectively. We observed only 18 brief nonconvulsive seizures in 11 of 29 control mice (median seizure count of 0) infused with vehicle (n = 4), normal CSF obtained from patients with noninflammatory central nervous system (CNS) conditions (n = 12), polyclonal rabbit IgG (n = 7), albumin (n = 3), and normal human IgG (n = 3). We did not observe memory deficits, anxiety-related behavior, or motor impairment measured at 2 weeks in animals treated with CSF from affected patients or rabbit IgG. Furthermore, there was no evidence of hippocampal cell loss or astrocyte proliferation in the same mice. Significance: Our findings indicate that autoantibodies can induce seizures in anti-NMDAR encephalitis and offer a model for testing novel therapies for refractory autoimmune seizures.

Original languageEnglish (US)
JournalEpilepsia
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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Encephalitis
Seizures
Cerebrospinal Fluid
Immunoglobulin G
Anti-N-Methyl-D-Aspartate Receptor Encephalitis
Rabbits
Memory Disorders
Anti-Idiotypic Antibodies
aspartic acid receptor
Anxiety
Intraventricular Infusions
Gliosis
Pyramidal Cells
Patch-Clamp Techniques
Inbred C57BL Mouse
Astrocytes
Autoantibodies
Immunoglobulins
Electroencephalography
Albumins

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Taraschenko, O., Fox, H. S., Pittock, S. J., Zekeridou, A., Gafurova, M., Eldridge, E., ... Dingledine, R. (2019). A mouse model of seizures in anti–N-methyl-d-aspartate receptor encephalitis. Epilepsia. https://doi.org/10.1111/epi.14662

A mouse model of seizures in anti–N-methyl-d-aspartate receptor encephalitis. / Taraschenko, Olga; Fox, Howard S.; Pittock, Sean J.; Zekeridou, Anastasia; Gafurova, Maftuna; Eldridge, Ember; Liu, Jinxu; Dravid, Shashank M.; Dingledine, Raymond.

In: Epilepsia, 01.01.2019.

Research output: Contribution to journalArticle

Taraschenko, O, Fox, HS, Pittock, SJ, Zekeridou, A, Gafurova, M, Eldridge, E, Liu, J, Dravid, SM & Dingledine, R 2019, 'A mouse model of seizures in anti–N-methyl-d-aspartate receptor encephalitis', Epilepsia. https://doi.org/10.1111/epi.14662
Taraschenko O, Fox HS, Pittock SJ, Zekeridou A, Gafurova M, Eldridge E et al. A mouse model of seizures in anti–N-methyl-d-aspartate receptor encephalitis. Epilepsia. 2019 Jan 1. https://doi.org/10.1111/epi.14662
Taraschenko, Olga ; Fox, Howard S. ; Pittock, Sean J. ; Zekeridou, Anastasia ; Gafurova, Maftuna ; Eldridge, Ember ; Liu, Jinxu ; Dravid, Shashank M. ; Dingledine, Raymond. / A mouse model of seizures in anti–N-methyl-d-aspartate receptor encephalitis. In: Epilepsia. 2019.
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AU - Gafurova, Maftuna

AU - Eldridge, Ember

AU - Liu, Jinxu

AU - Dravid, Shashank M.

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N2 - Objective: Seizures develop in 80% of patients with anti–N-methyl-d-aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality. Anti-NMDAR antibodies have been linked to memory loss in encephalitis; however, their role in seizures has not been established. We determined whether anti-NMDAR antibodies from autoimmune encephalitis patients are pathogenic for seizures. Methods: We performed continuous intracerebroventricular infusion of cerebrospinal fluid (CSF) or purified immunoglobulin (IgG) from the CSF of patients with anti-NMDAR encephalitis or polyclonal rabbit anti-NMDAR IgG, in male C57BL/6 mice. Seizure status during a 2-week treatment was assessed with video-electroencephalography. We assessed memory, anxiety-related behavior, and motor function at the end of treatment and assessed the extent of neuronal damage and gliosis in the CA1 region of hippocampus. We also performed whole-cell patch recordings from the CA1 pyramidal neurons in hippocampal slices of mice with seizures. Results: Prolonged exposure to rabbit anti-NMDAR IgG, patient CSF, or human IgG purified from the CSF of patients with encephalitis induced seizures in 33 of 36 mice. The median number of seizures recorded in 2 weeks was 13, 39, and 35 per mouse in these groups, respectively. We observed only 18 brief nonconvulsive seizures in 11 of 29 control mice (median seizure count of 0) infused with vehicle (n = 4), normal CSF obtained from patients with noninflammatory central nervous system (CNS) conditions (n = 12), polyclonal rabbit IgG (n = 7), albumin (n = 3), and normal human IgG (n = 3). We did not observe memory deficits, anxiety-related behavior, or motor impairment measured at 2 weeks in animals treated with CSF from affected patients or rabbit IgG. Furthermore, there was no evidence of hippocampal cell loss or astrocyte proliferation in the same mice. Significance: Our findings indicate that autoantibodies can induce seizures in anti-NMDAR encephalitis and offer a model for testing novel therapies for refractory autoimmune seizures.

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