Pathogenic human autoantibodies against NMDA receptor alter dendritic spine size

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis (NMDARE) is an autoimmune neurological disorder associated with anti-NMDAR antibodies (NMDAR-Ab), leading to synaptic dysfunction. While the effect of NMDAR-Ab on receptor internalization is well documented, its effect on dendritic protrusion morphology remains unclear. To investigate how NMDAR-Ab alters dendritic protrusion size and the associated molecular mechanisms using patient-derived sera. Cultured hippocampal neurons were treated with sera from patients with NMDARE. Protrusion size and the phosphorylation of cofilin, a regulator of actin dynamics, were also assessed. Exposure to NMDAR-Ab significantly decreased dendritic protrusion width and length while increasing protrusion density. Mechanistically, NMDAR-Ab decreased cofilin phosphorylation in dendritic protrusions. The reduction in spine size was partially reversible upon discontinuation of antibody treatment, except for the reduction in phosphorylated cofilin levels. NMDAR-Ab induced changes in dendritic protrusion size, along with alterations in actin dynamics, which may contribute to the cognitive and behavioral symptoms of NMDARE.