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

## TL;DR

This study suggests that increased release of glutamate in the brain may explain why people with anti-NMDAR encephalitis are more likely to have seizures.

## Contribution

This is the first study to demonstrate that elevated glutamate release may increase seizure susceptibility in anti-NMDAR encephalitis.

## Key findings

- Mice injected with GluN1359–378 showed increased seizure activity and epileptiform discharges.
- Exposure to serum from these mice increased neuronal action potentials and glutamate vesicular transporter expression.
- Reduced GluN1 surface expression and shortened seizure latency were observed in model mice.

## Abstract

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

Mice were injected with GluN1359–378 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 GluN1359–378, serum NMDAR‐Ab was detected. EEG recording revealed that 68.75% (11/16) of mice receiving GluN1359–378 exhibited epileptiform discharges. Moreover, the frequency of neuronal APs and mEPSCs following exposure to serum derived from mice receiving GluN1359–378 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 GluN1359–378 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 GluN1359–378 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.

Mice were injected with GluN1359–378 peptide to construct a model of anti‐NMDA receptor encephalitis. In anti‐NMDA receptor encephalitis, increased glutamate release may underlie the susceptibility of mice to seizures.