Investigating the effects of N-methyl-D-aspartate receptor autoantibodies on cortical oscillations in vitro

Abstract

N-methyl-D-Aspartate receptors (NMDARs) play a key role in memory formation and learning, and modulate gamma-frequency oscillations (-: 30-80Hz). Gamma-oscillations are important in perception, cognition and memory formation. They are disrupted in patients with schizophrenia, in whom NMDAR hypofunction has been posited, and in animal models of schizophrenia. Furthermore, NMDAR antagonists reduce -oscillation power and frequency in vitro. NMDA receptor antibody (NMDAR-Ab) encephalitis recapitulates some of the features seen with blockade or ablation of NMDARs, including anterograde memory loss and psychiatric symptoms. We hypothesised that patients’ autoantibodies against NMDARs could disrupt neuronal network activity and that this may be responsible for the neuropsychiatric symptoms experienced by patients. We examined the effect of acute and subacute NMDAR-Ab exposure on -frequency oscillations in the medial entorhinal cortex (mEC), using an in vitro rat brain slice preparation. We also performed the first comparison of four different diagnostic assays used for the detection of NMDAR-Abs. We found that: 1. Cell-based assay using live cells was 100% sensitive but poorly specific in the detection of NMDAR-Abs. Immunohistochemistry was 100% specific and also sensitive (85%). Two cell-based assays using fixed cells produced significant non-specific staining and had intermediate sensitivity and specificity values. 2. Acute exposure to purified IgG from patients with NMDAR-Ab encephalitis reduced the power of -frequency oscillations in the mEC but not in the hippocampus. 3. Immunoglobulin deposition was not found in the slices acutely exposed to patient or control IgG. ii 4. Subacute exposure to IgG by single intracerebral injection of either patient or control IgG did not alter mEC -oscillations ex vivo. No change in NMDAR-mediated responses was detected. 5. IgG uptake into presumed neurons was detected in slices from these animals, but it was not possible to co-localise the IgG to either excitatory neurones or inhibitory interneurones with certainty.