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)

1 Laboratoire de Neurologie Expérimentale
2 Department of Neurology
3 Centre de Référence Maladie Rare "Syndromes neurologiques Paranéoplasiques"
4 Neuro-oncologie et neuro-inflammation

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.

Domaines: Génétique

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, 2010, 5 (1), pp.31. ⟨10.1186/1750-1172-5-31⟩. ⟨inserm-00670158⟩