Abstract
Purpose: Limbic encephalitis associated with autoantibodies against N-methyl D-aspartate receptors (NMDARs) often presents with memory impairment. NMDARs are key targets for memory acquisition and retrieval, and have been mechanistically linked to its underlying process, synaptic plasticity. Clinically, memory deficits are largely compatible with a pre-dominantly hippocampus-dependent phenotype, which, in rodents, is principally involved in spatial memory. Previous studies confirmed the impaired spatial memory in the rat model of anti-NMDAR encephalitis. Here, we hypothesized that non-spatial memory functions, such as object recognition might also be affected in this model.Methods: We performed stereotactic intrahippocampal bolus injection of human cerebrospinal fluid (CSF) from anti-NMDAR encephalitis and control patients into the hippocampus of the anesthetized rat. After recovery for 1–8 days, hippocampal slices were prepared from these animals and NMDAR-dependent long-term potentiation was assessed at the Schaffer collateral-CA1 synapse. In addition, we performed behavioral analyses using the open field and novel object recognition tasks.Results: NMDAR-dependent long-term potentiation in the hippocampal CA1 area was significantly suppressed, indicating successful NMDAR dysfunction in this subfield. Spontaneous locomotor activity as well as anxiety-related behavior in the open field did not differ between NMDAR-CSF-treated and control animals. In the novel object recognition task, there were no differences in the motivation to approach objects. In contrast, we observed a significantly preferred exploration of the novel object only in control, but not in NMDAR-CSF-treated rats.Conclusion: These results indicate that NMDAR dysfunction obtained by intrahippocampal stereotactic injection does not alter locomotor or anxiety-related behavior. In addition, approach to an object or exploratory behavior in general are not affected either, but intact initial NMDAR-dependent processes might be involved in novel object recognition.
Highlights
Impaired short-term memory, cognitive symptoms, such as speech difficulties as well as psychiatric symptoms, such as anxiety, agitation, bizarre behavior, delusional thoughts, and hallucinations are major hallmarks in patients with limbic encephalitis, in particular when associated with autoantibodies against N-methyl D-aspartate receptors [NMDARs, [1,2,3]]
NMDARs are composed of GluN1 and GluN2 subunits, and it was demonstrated that NMDAR autoantibodies derived from patients’ cerebrospinal fluid (CSF) target the GluN1 extracellular domain leading to internalization of the entire NMDAR complex [2, 4,5,6]
Since there is overwhelming evidence that NMDARs are instrumental for memory acquisition and retrieval [reviewed by Nakazawa et al [7]], it is an attractive hypothesis that autoantibodies targeting NMDARs negatively interfere with NMDAR function and impair memory formation directly
Summary
Impaired short-term memory, cognitive symptoms, such as speech difficulties as well as psychiatric symptoms, such as anxiety, agitation, bizarre behavior, delusional thoughts, and hallucinations are major hallmarks in patients with limbic encephalitis, in particular when associated with autoantibodies against N-methyl D-aspartate receptors [NMDARs, [1,2,3]]. Non-spatial memory, such as novel object recognition (NOR) involves NMDAR function [16], but appears to be a crucial function of the perirhinal cortex [17,18,19,20,21] This behavioral task typically consists of a sample phase where the animal freely explores two objects in order to get familiarized, and following a variable delay, one of the two objects is replaced by a novel one [22, 23]. We hypothesized that CA1-LTP was compromised in this model
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
