In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction

We investigated the acute metabolic effects of patients' CSF and purified IgG injected in vivo. Injections were performed in CA1 area of Ammon's horn and in premotor cortex in rats.Patient's CSF increased the concentrations of glutamate in the extracellular space. The increase was dose-dependent and was dramatic with purified IgG. Patients' CSF impaired both the NMDA- and the AMPA-mediated synaptic regulation of glutamate, and did not affect the glial transport of glutamate. Blockade of GABA-A receptors was associated with a marked elevation of extra-cellular levels of glutamate following a pretreatment with patients' CSF.These results support a direct role of NMDA-R antibodies upon altering glutamatergic transmission. Furthermore, we provide additional evidence in vivo that NMDA-R antibodies deregulate the glutamatergic pathways and that the encephalitis associated with these antibodies is an auto-immune synaptic disorder.Antibodies to the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor have been identified in a newly-described encephalopathy [1]. One of the antigens corresponds to extracellular epitopes of NR1 subunit of the NMDA receptor (NMDA-R). Typically, patients are young women with teratoma of the ovary and presenting with acute psychiatric manifestations, seizures, dyskinesias, hypoventilation and autonomic instability [2]. Early removal of the teratoma followed by plasma exchange, intravenous immunoglobulins, and corticosteroids administration frequently results in neurological improvement and even full recovery [3].Recent studies showed that patients' antibodies cause a selective and reversible decrease in NMDA-R surface density and synaptic localization that correlates with antibody titers. The mechanism of this decrease is selective antibody-mediated crosslinking and internalization of the receptors. Furthermore, whole-cell patch clamp recordings of miniature excitatory postsynaptic currents in cultured rat hippocampal neurons showed that pat