Induction of Memory Deficit in Mice with Chronic Exposure to Cerebrospinal Fluid from Patients with Anti-<i>N</i>-Methyl-D-Aspartate Receptor Encephalitis

Abstract

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is now widely recognized and the patients with this disease show prominent psychiatric symptoms followed by seizures, respiratory failure, involuntary movement, autonomic instability, and amnesia. The anti-NMDAR antibody titer coincides with disease activity, and antibody-deprivation treatment ameliorates neurological symptoms. Previous studies have shown that clusters of NMDARs on the neuronal surface decrease in density upon incubation with the cerebrospinal fluid from patients (NMDAR-CSF), and that the induction of long-term potentiation, a cellular mechanism underlie learning and memory processes, was suppressed with NMDAR-CSF. In this study, we exposed mice to NMDAR-CSF in an attempt to reproduce the human symptoms in mice. CSF was continuously administered via a cannula placed in the lateral ventricle of the mouse that connected to an osmotic pump transplanted in the back of the mouse. From day 8-18, we evaluated the behavior of the mice using standardized tests that were performed serially. Mice exposed to NMDAR-CSF showed impaired spatial memory, as detected with the Morris water maze test. Brain tissue from mice with memory disturbances had decreased content of NMDAR protein in the hippocampal area shown by immunohistochemistry, which is consistent with the anti-NMDAR antibodies affect the expression and function of NMDARs, resulting in anti-NMDAR encephalitis-like symptoms. Also, the mice treated with the NMDAR-CSF did not show inflammatory cell infiltration or neuron loss in their brain tissue and this lack of nervous tissue destruction is encouraging as it is consistent with the idea that this disease can be treated through immunotherapy.

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

“…24 In addition, both short-term and prolonged administration of patients' CSF to rodents 38 led to the impairment of memory and learning. The lack of memory impairment was consistent with the previous findings 49 and could have been due to testing prior to the peak worsening. However, because a strong preference for the novel object was not observed in control mice, the present assay was likely not sufficiently sensitive to assess nonspatial memory in this model.…”

“…Another possibility for the lack of expected response in the control animals was an iatrogenic consequence of extensive cranial surgery. The lack of memory impairment was consistent with the previous findings 49 and could have been due to testing prior to the peak worsening. 21 Alternatively, the novel object paradigm applied in our study was not sensitive enough to reveal the differences between the 3 treatment groups in the setting of additional cerebral instrumentation.…”

Antibody-Mediated Encephalitis

“…36 The pathogenicity of NMDAR antibodies from affected patients has been suggested in other experimental models. 42,43 No animal models are available for other autoimmune encephalitides.…”

N-Methyl-D-aspartate receptor antibody could be a cause of catatonic symptoms in psychiatric patients: case reports and methods for detection

“…GluN1 and GluN2 co-transfected cells have been used for anti-NMDAR antibody measurement (tetramer cell-based assay [CBA]; Figure 1 ). 15 …”