Human N-methyl-d-aspartate receptor antibodies alter memory and behavior in a passive ventricular murine infusion model

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a disorder that causes neuropsychiatric symptoms with prominent memory and behavioral impairment. Antibodies react with the N-terminal domain of the GluN1 subunit leading to selective and reversible internalization of cell-surface NMDAR. These effects and the frequent response to immunotherapy have suggested an antibody-mediated pathogenesis, but to date there is no animal model showing that patients' antibodies cause memory and behavioral deficits. To develop such a model, C57BL6/J mice underwent placement of ventricular catheters connected to osmotic pumps, which delivered a continuous infusion of patients or control CSF (flow rate 0.25 μl/h, 14 days). During and after the infusion period standardized tests were applied, including tasks to assess memory (novel object recognition in open field and V-maze paradigms), anhedonic behaviors (sucrose preference test), depressive-like behaviors (tail suspension, and forced swimming tests), anxiety (black and white and elevated plus maze tests), aggressiveness (resident-intruder test), and locomotor activity (horizontal and vertical activity assessment).