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

Orphanet J Rare Dis. 2010 Nov 26;5:31. doi: 10.1186/1750-1172-5-31.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / administration & dosage
  • Autoantibodies / immunology*
  • Autoantibodies / metabolism
  • Autoimmune Diseases of the Nervous System / immunology
  • Autoimmune Diseases of the Nervous System / physiopathology*
  • Encephalitis / immunology
  • Encephalitis / physiopathology*
  • Glutamates / cerebrospinal fluid
  • Glutamates / metabolism*
  • Humans
  • Immunoglobulin G / administration & dosage
  • Immunoglobulin G / immunology*
  • Immunoglobulin G / metabolism
  • Male
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / immunology*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synaptic Transmission / immunology*
  • Synaptic Transmission / physiology

Substances

  • Autoantibodies
  • Glutamates
  • Immunoglobulin G
  • Receptors, N-Methyl-D-Aspartate