Elevated Release of Presynaptic Glutamate: The Potential Pathogenesis of Anti-NMDAR Encephalitis-Associated Seizures

The pathogenesis of anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDAR encephalitis)-associated seizures remains elusive.

Mice were injected with GluN1_359-378 peptide to construct a model of anti-NMDAR encephalitis. Next, the expression of NMDAR antibodies (NMDAR-Ab) was detected in serum samples. The electroencephalograms (EEGs) of mice were recorded. Afterward, neuronal action potentials (APs) and miniature excitatory postsynaptic currents (mEPSCs) were examined following exposure to serum derived from model mice. The expression levels of subunits of the NMDA receptor (GluN1, GluN2B) and glutamate vesicular transporter 1 (Vglut1) were quantified via Western blot analysis. Additionally, mice were injected with pentylenetetrazol (PTZ) to construct an in vivo model of status epilepticus (SE). Lastly, neurons exposed to mouse serum were incubated in a magnesium-free solution (Mg²⁺-free) for 1, 2, and 3 h, and APs were assessed.

Following the administration of immunogenic peptide GluN1_359-378, serum NMDAR-Ab was detected. EEG recording revealed that 68.75% (11/16) of mice receiving GluN1_359-378 exhibited epileptiform discharges. Moreover, the frequency of neuronal APs and mEPSCs following exposure to serum derived from mice receiving GluN1_359-378 was increased. The surface expression level of the GluN1 protein was significantly decreased, whereas that of the total Vglut1 protein was increased. Moreover, the seizure latency of mice receiving GluN1_359-378 was significantly shortened. Finally, after 1 to 2 h of incubation with Mg²⁺-free solution, the frequency of neuronal APs following exposure to serum derived from mice receiving GluN1_359-378 was increased.

To the best of our knowledge, this is the first study to demonstrate that increased glutamate release may increase seizure susceptibility in patients with anti-NMDAR encephalitis.