Anti-NMDA Receptor Encephalitis Weekly Newsletter

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the central nervous system associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to cerebrospinal fluid (CSF) from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Co-application of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite wash-out of PAMs prior to electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction.

Significance statement: Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden-onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy.

Anti–NMDA receptor (anti-NMDAR) encephalitis was first described in 20071 and is now recognized as one of the most common forms of encephalitis.2 Anti-NMDAR encephalitis is considered a multistage disease, characterized by nonspecific prodromal flu-like symptoms, followed by acute onset of psychiatric manifestations such as psychosis, delusions, hallucinations, anxiety, insomnia, repetitive behaviors, echolalia, and mutism. Patients at this stage generally present to either neurology or psychiatry services. This phase is usually followed by a change in level of alertness with periods of extreme agitation and catatonia along with the appearance of the classic orofacial and lingual dyskinesias or other movement disorders and pronounced autonomic instability. The combination of autonomic storms and coma often leads to a prolonged intensive care unit (ICU) admission. Patients—children in particular—can also develop focal or generalized seizures. Anti-NMDAR encephalitis can be associated with a tumor, especially ovarian teratomas in female patients older than 12 years. Brain MRI is normal in up to 67% of patients, whereas EEG is abnormal in 90% of patients.3 EEG findings are nonspecific and can include slowing, disorganization of the background, and electrographic seizures. The diagnosis is confirmed by the presence of NMDAR antibodies in the CSF.