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

Mario Manto 1, * Josep Dalmau 2 Adrien Didelot 3, 4 Véronique Rogemond 3, 4 Jérôme Honnorat 3, 4
* Auteur correspondant
1 Laboratoire de Neurologie Expérimentale
2 Department of Neurology
3 Centre de Référence Maladie Rare "Syndromes neurologiques Paranéoplasiques"
4 Neuro-oncologie et neuro-inflammation
Abstract : 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. CONCLUSION: 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.
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Orphanet Journal of Rare Diseases, BioMed Central, 2010, 5 (1), pp.31. 〈10.1186/1750-1172-5-31〉
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Mario Manto, Josep Dalmau, Adrien Didelot, Véronique Rogemond, Jérôme Honnorat. In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction.. Orphanet Journal of Rare Diseases, BioMed Central, 2010, 5 (1), pp.31. 〈10.1186/1750-1172-5-31〉. 〈inserm-00670158〉

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