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

Abstract

AbstractObjectiveWe 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.MethodsMonoclonal 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.ResultsAs 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.SignificanceThese 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.