In vitro and in vivo models of autoimmune synaptopathies

• Autor(a) principal: Serafim, Ana Beatriz de Araújo e Gama
• Data de Publicação: 2022
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10348/11757
• topic: anti-NMDAR encephalitis; animal model

Encephalitis mediated by autoantibodies against the N-methyl-D-aspartate receptor (NMDAR) is a neurological disorder that presents a rapid progression of neuropsychiatric manifestations. Patients manifest with memory impairment and severe behavioral alterations. Despite being the best studied of these pathologies, all the animal models developed up to date do not reproduce fully the behavioral and molecular alterations seen in the human disease, including both the immunological and neurological changes. To better model the disease and study the effect of NMDAR antibodies in vivo we have developed an immune-mediated murine model. In this model, female eightweek-old C57BL/6J mice were immunized on days 1 and 28 with 200 µg GluN1 356-385 or saline in AddaVax adjuvant and Bordetella Pertussis Toxin. With this murine model, we realized standard behavioral tests and brain tissue studies. We observed that NMDAR mice, but not control mice, developed memory impairment, acute psychotic-like behavior, and chronic depressive-like behavior. This behavioral phenotype was accompanied by antibody-producing B cell and T-helper inflammatory infiltrates in the brain, NMDAR brain-bound antibodies, and a decrease in total and synaptic NMDAR clusters. Our results demonstrate that active immunization with GluN1 356-385 peptide led to the development of an animal model that more closely reproduces the clinical and synaptic alterations of the patients. This model is reliable to test pharmacological therapies in vivo.