Defective callosal termination underlies the long-term behavioral deficits in NMDA receptor antibody encephalitis mouse model

Abstract

AbstractNMDA receptor antibody encephalitis (NMDAR-AE) is characterized by cerebrospinal fluid (CSF)-resident anti-NMDA receptor autoantibodies that cause a wide range of neurological manifestations. Although many symptoms are responsive to immunotherapy, behavioral deficits persist, especially in young patients. However, the underlying mechanisms of these long-lasting impairments are unknown. Here, we used a patient-derived GluN1-specific monoclonal antibody (mAb) to interrogate the underlying mechanisms of long-lasting sensory-motor impairments. Transient exposure to this mAb led to excess callosal projections in somatosensory cortex and resulted in permanent callosal axon alterations in mice. Importantly, these mice displayed persistent fine movement impairments which were similar to those in NMDAR-AE patients. Notably, the severity of these behavioral deficits was tightly correlated with the severity of callosal axon alterations. At the injection site, the anti-GluN1 autoantibody significantly decreased EPH receptor B2 (EPHB2) expression, a regulator of commissural projections, indicating EPHB2’s essential role in this phenotype. Our studies reveal important insights into the cellular and molecular basis for persistent sensory-motor deficits in NMDAR-AE.