RESUMO
BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesia, and seizures. However, the underlying mechanisms of this disease remain unclear, in part because of a lack of suitable animal models. METHODS: This study describes a novel female C57BL/6 mouse model of anti-NMDAR encephalitis that was induced by active immunization against NMDARs using an amino terminal domain (ATD) peptide from the GluN1 subunit (GluN1356-385). RESULTS: Twelve weeks after immunization, the immunized mice showed significant memory loss. Furthermore, antibodies from the cerebrospinal fluid of immunized mice decreased the surface NMDAR cluster density in hippocampal neurons which was similar to the effect induced by the anti-NMDAR encephalitis patients' antibodies. Immunization also impaired long-term potentiation at Schaffer collateral-CA1 synapses and reduced NMDAR-induced calcium influx. CONCLUSION: We established a novel anti-NMDAR encephalitis model using active immunization with peptide GluN1356-385 targeting the ATD of GluN1. This novel model may allow further research into the pathogenesis of anti-NMDAR encephalitis and aid in the development of new therapies for this disease.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/induzido quimicamente , Proteínas do Tecido Nervoso/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Receptores de N-Metil-D-Aspartato/administração & dosagem , Vacinação/efeitos adversos , Sequência de Aminoácidos , Animais , Encefalite Antirreceptor de N-Metil-D-Aspartato/genética , Encefalite Antirreceptor de N-Metil-D-Aspartato/imunologia , Autoanticorpos/genética , Autoanticorpos/imunologia , Células Cultivadas , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Ratos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/imunologia , Vacinação/métodosRESUMO
Glutamate-mediated neurodegeneration resulting from excessive activation of glutamate receptors is recognized as one of the major causes of various neurological disorders such as Alzheimer's and Huntington's diseases. However, the underlying mechanisms in the neurodegenerative process remain unidentified. Here, we investigate the real-time dynamic structural and mechanical changes associated with the neurodegeneration induced by the activation of N-methyl-D-aspartate (NMDA) receptors (a subtype of glutamate receptors) at the nanoscale. Atomic force microscopy (AFM) is employed to measure the three-dimensional (3-D) topography and mechanical properties of live SH-SY5Y cells under stimulus of NMDA receptors. A significant increase in surface roughness and stiffness of the cell is observed after NMDA treatment, which indicates the time-dependent neuronal cell behavior under NMDA-mediated neurodegeneration. The present AFM based study further advance our understanding of the neurodegenerative process to elucidate the pathways and mechanisms that govern NMDA induced neurodegeneration, so as to facilitate the development of novel therapeutic strategies for neurodegenerative diseases.