Encephalitis has an estimated prevalence of ≤0.01%. Even with extensive diagnostic work-up, an infectious etiology is identified or suspected in <50% of cases, suggesting a role for etiologically unclear, noninfectious processes. Mild
encephalitis runs frequently unnoticed, despite slight
neuroinflammation detectable postmortem in many neuropsychiatric illnesses. A widely unexplored field in humans, though clearly documented in rodents, is genetic
brain inflammation, particularly that associated with myelin abnormalities, inducing primary white matter
encephalitis. We hypothesized that "
autoimmune encephalitides" may result from any
brain inflammation concurring with the presence of brain
antigen-directed
autoantibodies, e.g., against
N-methyl-D-aspartate-receptor NR1 (NMDAR1-AB), which are not causal of, but may considerably shape the
encephalitis phenotype. We therefore immunized young female Cnp-/- mice lacking the structural
myelin protein 2'-3'-cyclic
nucleotide 3'-phosphodiesterase (Cnp) with a "cocktail" of
NMDAR1 peptides. Cnp-/- mice exhibit early low-grade
inflammation of white matter tracts and blood-brain barrier disruption. Our novel mental-time-travel test disclosed that Cnp-/- mice are compromised in what-where-when orientation, but this episodic memory readout was not further deteriorated by NMDAR1-AB. In contrast, comparing wild-type and Cnp-/- mice without/with NMDAR1-AB regarding hippocampal learning/memory and motor balance/coordination revealed distinct stair patterns of behavioral pathology. To elucidate a potential contribution of oligodendroglial NMDAR downregulation to NMDAR1-AB effects, we generated conditional NR1 knockout mice. These mice displayed normal Morris water maze and mental-time-travel, but beam balance performance was similar to immunized Cnp-/-. Immunohistochemistry confirmed
neuroinflammation/neurodegeneration in Cnp-/- mice, yet without add-on effect of NMDAR1-AB. To conclude, genetic
brain inflammation may explain an encephalitic component underlying autoimmune conditions.