| dc.description.abstracteng | The anti-NMDAR encephalitis (NMDARE) is an autoimmune condition with so far unclear etiology and pathogenesis. It manifests with a heterogeneous clinical disease course and is diagnosed based on the presence of NMDAR1-autoantibodies (NMDAR1-AB) of the IgG class in patients’ cerebrospinal fluid. The associated NMDAR1-AB bind and cross-link surface N-methyl-D-aspartate receptors (NMDAR), resulting in NMDAR internalization and hypofunction. On a theoretical basis, the presence of NMDAR1-AB could contribute to the psychopathological phenotype of NMDARE patients and explain why psychoses and behavioral alterations are more frequent in NMDARE as compared to other encephalitides. However, the pathophysiological role of NMDAR1-AB in neuroinflammatory contexts has, so far, not been formally differentiated from the underlying pathomechanism(s) and previously established NMDARE-related animal models lack the neuroinflammatory component of the disease. To systematically disentangle the relative contribution of NMDAR1-AB from neuroinflammatory and neurodegenerative processes of encephalitides, core features of the anti-NMDAR encephalitis were modeled in mice. This was achieved by combining a standardized spatiotemporally defined gray matter inflammation mouse model (‘DTA’ mice), which was deeper characterized as part of this thesis, with a previously established immunization against a cocktail of extracellular GluN1-specific peptides that induces functional NMDAR1-AB expression. In addition, effects of NMDAR1-AB on white matter inflammation were investigated in Cnp knockout mice. Lastly, a replication study of a previously published immunization protocol was conducted with the aim to investigate the pathogenesis of anti-NMDAR encephalitis in wildtype mice.
In summary, DTA mice, independent of NMDAR1-AB, displayed key aspects of the anti-NMDAR encephalitis, namely (1) acute onset, (2) neuroinflammation in gray matter regions, prominently but not exclusively affecting the hippocampus, (3) blood-brain barrier impairment, and (4) pronounced learning/memory deficits. Consistent with NMDAR antagonism, the presence of NMDAR1-AB exacerbated hyperlocomotion, a psychosis-like readout, in DTA mice without add-on effects on neuroinflammation. Similarly, NMDAR1-AB did not alter white matter inflammation in Cnp knockout mice but exacerbated the behavioral pathology. Noteworthy, NMDAR1-AB affected distinct behavioral domains in gray and white matter inflammation, suggesting that the pathophysiological role of NMDAR1-AB depends on the underlying pathology, potentially due to distinct NMDAR1-AB distribution across the central nervous system which is largely related to blood-brain barrier (dys)function. Consistent with previous reports, extensive behavioral phenotyping did not reveal any effects of NMDAR1-AB in healthy control mice with an intact blood-brain barrier. Importantly, neither immunization against a cocktail of GluN1-specific peptides nor against GluN1359-378 alone induced neuroinflammation in mice. In conclusion, NMDAR1-AB can modulate the behavioral phenotypes of underlying encephalitides but are not sufficient for the induction or exacerbation of neuroinflammation. | de |