Anti-NMDAR encephalitis (NMDARe) is a disorder mediated by antibodies against the GluN1 subunit of NMDAR. Patients develop severe neuropsychiatric symptoms that usually improve with immunotherapy, although very slowly. To better understand the neuro-immunobiology of the disease and how different treatments might work, we aimed to develop an animal model that reproduced most of the symptoms and their protracted clinical course. Eight-week-old female mice (C57BL/6J) were immunized (days 1 and 28) with GluN1356-385 peptide or saline with AddaVax adjuvant and Pertussis Toxin. After developing symptoms (acute phase, ~day 35), subsets of mice were treated with anti-CD20 with or without additional treatment with a positive allosteric modulator (PAM, SGE-301) of NMDAR (days 45-71, chronic phase). GluN1-antibody synthesis, effects on densityand function of NMDAR, and brain immunological infiltrates were assessed with immunohistochemistry, calcium imaging, synaptic confocal imaging, electrophysiology, flow cytometry, and behavioral tests. Immunized mice developed serum and CSF NMDAR-antibodies and brain inflammatory infiltrates, mainly B- and plasma cells. Untreated mice exhibited reduced synaptic NMDAR density, impaired long-term potentiation (LTP), psychotic-like behavior, anxiety, depression, memory impairment, reduced seizure threshold, and (~15% of mice) stereotyped movements, from day 34-71. Anti-CD20-treated mice showed reduced brain B cells on day 42 (with recovery of NMDAR density, LTP, and symptoms), and B cell repopulation by day 70 (with memory worsening). PAM treatment alone improved most pathogenic effects, and if used after the anti-CD20, ensured stable symptom recovery. These findings provide a useful model to assess the neuro-immunobiology of NMDARe, and potential novel treatment strategies.