Role of Adult Neurogenesis in Memory Loss in a Mouse Model of NMDA Receptor-mediated Epilepsy
Abstract number :
1.075
Submission category :
1. Basic Mechanisms / 1E. Models
Year :
2024
Submission ID :
829
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Olga Taraschenko, MD, PhD – University of Nebraska Medical Center
Howard Fox, MD, PhD – University of Nebraska Medical Center
Priscilla Heliso, BS – University of Nebraska Medical Center
Fetweh Al-Saleem, BS – Lankenau Institute for Medical Research
Scott Dessain, MD – Lankenau Institute for Medical Research
Woo-Yang Kim, PhD – Kent State University
Mystera Samuelson, PhD – University of Nebraska Medical Center
Raymond Dingledine, PhD, Professor – Emory University School of Medicine
Rationale: Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) results in chronic epilepsy and permanent cognitive impairment. One of the possible causes of cognitive loss in anti-NMDARE could be aberrant neurogenesis, an established contributor to memory loss in idiopathic drug-resistant epilepsy. We developed a mouse model of anti-NMDARE and showed that mice exposed to patient-derived anti-NMDAR antibodies developed seizures and memory loss. In the present study, we assessed the immediate and delayed effects of anti-NMDAR antibodies on cognitive phenotype and examined the corresponding changes in hippocampal neurogenesis.
Methods: Monoclonal anti-NMDAR antibodies derived from B cells of a patient with anti-NMDARE and seizures (1D1, 5F5, and 2G6; 0.2 μg/μl) or control 6A IgG1λ human monoclonal antibodies which do not bind GluN1 were continuously infused into the lateral ventricle of male C56BL/6J mice (8-12 weeks) via osmotic minipumps for 2 weeks. Bromodeoxyuridine (BrdU, 50 mg/kg, i.p., daily) was injected on days 2-12 of the infusion when seizures were demonstrated previously. The motor and anxiety phenotypes were assessed using the open field paradigm while 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. Immunohistochemistry was performed to detect granule cells (Prox-1+) and progenitor cells (DCX+) at these time points and confocal or light microscopy was applied to count the cells and determine their spatial distribution.
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 a sustained 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.
Conclusions: 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 adult hippocampal neurogenesis. Interventions directed at the manipulation of neuronal plasticity in patients with encephalitis and cognitive loss may be protective and therapeutically relevant.
Funding: NIH P20GM130447
DHHS LB606
Basic Mechanisms