MyD88-mediated signaling is critical for the generation of seizure responses and cognitive impairment in a model of anti-N-methyl-D-aspartate receptor encephalitis

Olga Taraschenko, Howard S. Fox, Ember Eldridge, Priscilla Heliso, Fetweh Al-Saleem, Scott Dessain, George Casale, Gregory Willcockson, Kayley Anderson, Wenyi Wang, Raymond Dingledine

Research output: Contribution to journalArticlepeer-review


Objective: We previously demonstrated that interleukin-1 receptor-mediated immune activation contributes to seizure severity and memory loss in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. In the present study, we assessed the role of the myeloid differentiation primary response gene 88 (MyD88), an adaptor protein in Toll-like receptor signaling, in the key phenotypic characteristics of anti-NMDAR encephalitis. Methods: Monoclonal anti-NMDAR antibodies or control antibodies were infused into the lateral ventricle of MyD88 knockout mice (MyD88−/−) and control C56BL/6J mice (wild type [WT]) via osmotic minipumps for 2 weeks. Seizure responses were measured by electroencephalography. Upon completion of the infusion, the motor, anxiety, and memory functions of the mice were assessed. Astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adaptor molecule 1 [Iba-1]) activation and transcriptional activation for the principal inflammatory mediators involved in seizures were determined using immunohistochemistry and quantitative real-time polymerase chain reaction, respectively. Results: As shown before, 80% of WT mice infused with anti-NMDAR antibodies (n = 10) developed seizures (median = 11, interquartile range [IQR] = 3–25 in 2 weeks). In contrast, only three of 14 MyD88−/− mice (21.4%) had seizures (0, IQR = 0–.25, p =.01). The WT mice treated with antibodies also developed memory loss in the novel object recognition test, whereas such memory deficits were not apparent in MyD88−/− mice treated with anti-NMDAR antibodies (p =.03) or control antibodies (p =.04). Furthermore, in contrast to the WT mice exposed to anti-NMDAR antibodies, the MyD88−/− mice had a significantly lower induction of chemokine (C-C motif) ligand 2 (CCL2) in the hippocampus (p =.0001, Sidak tests). There were no significant changes in the expression of GFAP and Iba-1 in the MyD88−/− mice treated with anti-NMDAR or control antibodies. Significance: These findings suggest that MyD88-mediated signaling contributes to the seizure and memory phenotype in anti-NMDAR encephalitis and that CCL2 activation may participate in the expression of these features. The removal of MyD88 inflammation may be protective and therapeutically relevant.

Original languageEnglish (US)
Pages (from-to)1475-1487
Number of pages13
Issue number5
StatePublished - May 2024


  • MyD88 protein
  • Toll-like receptors
  • anti-NMDA receptor encephalitis
  • autoimmune seizures
  • cytokines
  • memory loss
  • neuroinflammation
  • neuronal autoantibodies

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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