In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction.
BACKGROUND
A severe encephalitis that associates with auto-antibodies to the NR1 subunit of the NMDA receptor (NMDA-R) was recently reported. Patients' antibodies cause a decrease of the density of NMDA-R and synaptic mediated currents, but the in vivo effects on the extracellular glutamate and glutamatergic transmission are unknown.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
FNRS-Laboratoire de Neurologie Expérimentale, ULB, Belgium. mmanto@ulb.ac.be
Mario
M
Manto
Josep
J
Dalmau
Adrien
A
Didelot
Véronique
V
Rogemond
Jérôme
J
Honnorat
D000818:Animals; D001323:Autoantibodies / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D020274:Autoimmune Diseases of the Nervous System / Q000276:immunology / Q000503:physiopathology*; D004660:Encephalitis / Q000276:immunology / Q000503:physiopathology*; D005971:Glutamates / Q000134:cerebrospinal fluid / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology* / Q000378:metabolism; D009435:Synaptic Transmission / Q000276:immunology* / Q000502:physiology
D001323:Autoantibodies; D005971:Glutamates; D007074:Immunoglobulin G; D016194:Receptors, N-Methyl-D-Aspartate