دورية أكاديمية
Memory loss and aberrant neurogenesis in mice exposed to patient anti-N-methyl-d-aspartate receptor antibodies.
| العنوان: | Memory loss and aberrant neurogenesis in mice exposed to patient anti-N-methyl-d-aspartate receptor antibodies. |
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| المؤلفون: | Taraschenko O; Department of Neurological Sciences, Division of Epilepsy, University of Nebraska Medical Center, Omaha, NE, United States of America. Electronic address: olha.taraschenko@unmc.edu., Fox HS; Department of Neurological Sciences, Division of Epilepsy, University of Nebraska Medical Center, Omaha, NE, United States of America., Heliso P; Department of Neurological Sciences, Division of Epilepsy, University of Nebraska Medical Center, Omaha, NE, United States of America., Al-Saleem F; Lankenau Institute for Medical Research, Wynnewood, PA, United States of America., Dessain S; Lankenau Institute for Medical Research, Wynnewood, PA, United States of America., Kim WY; Department of Biological Sciences, Kent State University, Kent, OH, United States of America., Samuelson MM; Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, NE, United States of America., Dingledine R; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, United States of America. |
| المصدر: | Experimental neurology [Exp Neurol] 2024 Aug; Vol. 378, pp. 114838. Date of Electronic Publication: 2024 May 25. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Academic Press Country of Publication: United States NLM ID: 0370712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2430 (Electronic) Linking ISSN: 00144886 NLM ISO Abbreviation: Exp Neurol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Orlando Fl : Academic Press Original Publication: New York. |
| مواضيع طبية MeSH: | Anti-N-Methyl-D-Aspartate Receptor Encephalitis*/immunology , Doublecortin Protein* , Hippocampus*/pathology , Maze Learning*/physiology , Maze Learning*/drug effects , Memory Disorders*/etiology , Neurogenesis*/drug effects , Neurogenesis*/physiology, Animals ; Humans ; Male ; Mice ; Autoantibodies/immunology ; Disease Models, Animal ; Mice, Inbred C57BL ; Receptors, N-Methyl-D-Aspartate/immunology ; Receptors, N-Methyl-D-Aspartate/metabolism |
| مستخلص: | Objective: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis results in chronic epilepsy and permanent cognitive impairment. One of the possible causes of cognitive impairment in anti-NMDAR could be aberrant neurogenesis, an established contributor to memory loss in idiopathic drug-resistant epilepsy. We developed a mouse model of anti-NMDAR encephalitis and showed that mice exposed to patient anti-NMDAR antibodies for 2 weeks developed seizures and memory loss. In the present study, we assessed the delayed effects of patient-derived antibodies on cognitive phenotype and examined the corresponding changes in hippocampal neurogenesis. Methods: Monoclonal anti-NMDAR antibodies or control antibodies were continuously infused into the lateral ventricle of male C56BL/6J mice (8-12 weeks) via osmotic minipumps for 2 weeks. The motor and anxiety phenotypes were assessed using the open field paradigm, and hippocampal memory and learning were assessed using the object location, Y maze, and Barnes maze paradigms during weeks 1 and 3-4 of antibody washout. The numbers of newly matured granule neurons (Prox-1+) and immature progenitor cells (DCX+) as well as their spatial distribution within the hippocampus were assessed at these time points. Bromodeoxyuridine (BrdU, 50 mg/kg, i.p., daily) was injected on days 2-12 of the infusion, and proliferating cell immunoreactivity was compared in antibody-treated mice and control mice during week 4 of the washout. Results: Mice infused with anti-NMDAR antibodies demonstrated spatial memory impairment during week 1 of antibody washout (p = 0.02, t-test; n = 9-11). Histological analysis of hippocampal sections from these mice revealed an increased ectopic displacement of Prox-1+ cells in the dentate hilus compared to the control-antibody-treated mice (p = 0.01; t-test). Mice exposed to anti-NMDAR antibodies also had an impairment of spatial memory and learning during weeks 3-4 of antibody washout (object location: p = 0.009; t-test; Y maze: p = 0.006, t-test; Barnes maze: p = 0.008, ANOVA; n = 8-10). These mice showed increased ratios of the low proliferating (bright) to fast proliferating (faint) BrdU+ cell counts and decreased number of DCX+ cells in the hippocampal dentate gyrus (p = 0.006 and p = 0.04, respectively; t-tests) suggesting ectopic migration and delayed cell proliferation. Significance: These findings suggest that memory and learning impairments induced by patient anti-NMDAR antibodies are sustained upon removal of antibodies and are accompanied by aberrant hippocampal neurogenesis. Interventions directed at the manipulation of neuronal plasticity in patients with encephalitis and cognitive loss may be protective and therapeutically relevant. Competing Interests: Declaration of competing interest All the authors have approved the manuscript and agree with submission to Experimental Neurology. There are no conflicts of interest to declare. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: (Copyright © 2024 Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Aberrant neurogenesis; Anti-NMDA receptor encephalitis; Antibody-induced seizures; Autoimmune encephalitis; Cognitive failure in encephalitis; Memory loss |
| المشرفين على المادة: | 0 (Autoantibodies) 0 (Dcx protein, mouse) 0 (Doublecortin Protein) 0 (Receptors, N-Methyl-D-Aspartate) |
| تواريخ الأحداث: | Date Created: 20240527 Date Completed: 20240614 Latest Revision: 20240621 |
| رمز التحديث: | 20240622 |
| DOI: | 10.1016/j.expneurol.2024.114838 |
| PMID: | 38801989 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1090-2430 |
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| DOI: | 10.1016/j.expneurol.2024.114838 |