What Are the Proposed Mechanisms Contributing to the Manifestations of Anti-NMDAR Encephalitis?

Abstract

Anti-NMDA receptor (NMDAR) encephalitis is the first well-characterized autoimmune disorder caused by autoantibodies directed against neuronal surface proteins in the CNS.^1-3 Initially described in patients with ovarian teratoma,² this disorder typically presents with the rapid onset of a characteristic constellation of clinical features, including severe memory impairment, prominent psychiatric and behavioral disturbances, insomnia, seizures, facial dyskinesia and other abnormal movements, hypoventilation, and autonomic dysfunction.^1-4 These clinical features are consistent with the diverse roles of NMDAR signaling within the CNS, involving both glutamatergic neurons and local GABAergic interneurons across circuits that control cognition, behavior, and survival.^5,6 Several experimental models have investigated the mechanisms by which NMDAR autoantibodies result in synaptic dysfunction and contribute to the clinical manifestations of anti-NMDAR encephalitis.^7-10 These studies demonstrate that the autoantibodies crosslink NMDARs, disrupting their surface trafficking and promoting receptor internalization. This leads to a reduction in synaptic and extrasynaptic NMDAR density and NMDAR-mediated currents, disrupting the excitatory-inhibitory synaptic balance and inducing changes in hippocampal and cortical γ oscillations.^7,11,12.