Neuronal NMDAR Currents of the Hippocampus and Learning Performance in Autoimmune Anti-NMDAR Encephalitis and Involvement of TNF-α and IL-6

Abstract

Among autoimmune encephalitis, patients with anti-N-methyl D- aspartate receptor (NMDAR) encephalitis typically present epileptic seizures, memory deficits and psychiatric symptoms. However, the signal mechanisms leading to the functional disorders of autoantibodies are largely unclear. In this study, anti-NMDAR antibody was administered into dentate gyri against the NR1 subunit of the NMDAR. The purpose of the study examined the effects of pro-inflammatory tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) on neuronal NMDAR currents of the hippocampus in rats with anti-NMDAR encephalitis and we further determined the role played by TNF-α and IL-6 in modulating learning performance. In results, we observed a decrease in amplitude of the NMDAR-mediated excitatory postsynaptic currents (NMDAR-EPSCs) in the hippocampal neurons of animals treated with anti-NMDAR. In those rats with anti-NMDAR, we also observed impaired learning performance in the Morris water maze and spatial working memory test. Of note, cerebral infusion of TNF-α and IL-6 worsened NMDAR-EPSCs and this was accompanied with exaggeration of impaired learning performance. In conclusion, our findings suggest that the role played by neuroinflammation in exacerbating the memory impairment found in animals treated with anti-NMDAR. Anti-inflammation is a potential target in improving the memory impairment induced by anti-NMDA encephalitis.

Cerebrospinal Fluid Osteopontin and Inflammation-Associated Cytokines in Patients With Anti-N-Methyl-D-Aspartate Receptor Encephalitis

“…In addition, anti-NMDAR antibodies have been suggested to have a correlation with outcome or relapses by some articles (7) but not others (8). Cytokines mentioned previously like interleukin (IL)-6, tumor necrosis factor (TNF)-α have been proposed to play important roles in the pathogenesis of this disease (9)(10)(11). We also have reported increased inflammatory cytokines in cerebrospinal fluid (CSF) in the acute stage of anti-NMDAR encephalitis (12,13).…”

Cognitive impact of neuronal antibodies: encephalitis and beyond

“…Prominent memory deficits remain with spatial disorientation 42 . Executive function, attention, semantic and phonemic fluency is also impaired 40,55 Verbal, visuospatial and working memory deficits persist 40 Furthermore, in vivo infusion of NMDAR antibodies reduces excitatory postsynaptic currents in rat hippocampal neurons and simultaneously impairs learning and spatial working memory 20 . Infusion of inflammatory cytokines also reduced excitatory postsynaptic currents and led to further impairment in learning performance suggesting there may be other additive factors influencing cognitive dysfunction 15 .…”

“…Accordingly, NMDAR-dependent LTP is depressed in mouse hippocampal slices with prolonged exposure to CSF from patients with NMDAR encephalitis 19 . Furthermore, in vivo infusion of NMDAR antibodies reduces excitatory postsynaptic currents in rat hippocampal neurons and simultaneously impairs learning and spatial working memory 20 . Infusion of inflammatory cytokines also reduced excitatory postsynaptic currents and led to further impairment in learning performance suggesting there may be other additive factors influencing cognitive dysfunction 15 .…”

<p>Association Between IL-6 and Seizure Recurrence in Patients with the First Post-Ischemic Stroke Seizure</p>

“…43 Fang et al 44 demonstrated that IL-6 could inhibit neuronal necrosis and apoptosis through decreasing cytosolic Ca 2+ overload induced by N-methyl D-aspartate, implying a neuroprotection of IL-6. However, Wang et al 45 found that a chronic infusion of IL-6 could attenuate miniature excitatory postsynaptic currents regulated by N-methyl D-aspartate receptor in the hippocampal neurons of rats treated with anti-N-methyl D-aspartate receptor, which exacerbated memory impairment of rats. Therefore, IL-6 may bidirectionally impose influence on memory and synaptic plasticity.…”