Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice (1)
Memory, learning, and behaviour depend on the proper function of the excitatory glutamate N-methyl D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and underlying mechanisms of synaptic plasticity. a novel disorder (anti-NMDAR encephalitis) that occurs with highly specific antibodies against extracellular epitopes located at the amino terminal domain of the GluN1 subunit of NMDAR. Symptoms are usually accompanied by systemic and intrathecal synthesis of antibodies, the latter likely produced by plasma cells contained in brain inflammatory infiltrates.The density of NMDAR was also significantly reduced in the hippocampus of rats infused with patients’ antibodies, a finding comparable to that observed in the hippocampus of autopsied patients.
Appropriate ventricular placement of the catheters was assessed in randomly selected mice injecting methylene blue through the catheters.
The memory deficit became significant on Day 10 and was maximal on Day 18 (4 days after the infusion of CSF had stopped). On Day 25, the object recognition index had normalized and was similar to that of animals treated with control CSF. Mice infused with patients’ CSF and tested during the infusion period (Day 10) had less preference for sucrose compared with mice infused with control CSF. The tail suspension test, performed on Day 12, showed that animals infused with patients’ CSF had longer periods of immobility compared with those infused with control CSF.
No significant differences were noted in tests of anxiety (black and white test, elevated plus maze test), aggression (resident-intruder test) and locomotor activity.
The distribution of IgG immunostaining predominated in regions with high density of NMDAR, mainly the hippocampus. Upon quantification of immunostaining, the maximal antibody binding was identified in mice sacrificed on Day 18, which had received 14 days of CSF infusion, compared with mice sacrificed on Days 5 or 13. in animals infused with patients’ CSF the presence of hippocampal IgG was visible as a punctate immunolabelling on the surface of neurons and neuronal processes in contrast to mice infused with control CSF where minor amounts of IgG reactivity without preference for neuronal structures were noted. In addition, the amount of human IgG bound to all selected re- gions of hippocampus was significantly higher than in the control group.
The IgG extracted from hippocampus of mice infused with patients’ CSF reacted specifically with GluN1. The NMDAR antibody concentration in the extracts correlated with the duration of infusion of CSF; it increased until Day 13, reached the maximal concentration on Days 13–18, and decreased afterwards.
Animals infused with patients’ CSF had on Days 13 and 18 a significant decrease of the density of total and synaptic hippocampal NMDAR clusters followed by a gradual recovery after Day 18.
Immunoblot analysis of total protein extracted from hippocampus showed that on Days 13 and 18, mice infused with patients’ CSF had a significant decrease of total NMDAR protein concentration compared with mice infused with control CSF.
C57BL6/J mice strain is one of the most resistant to develop seizures.
