Investigating the Effects of NMDAR and LGI1 Antibodies on Absence Seizures: Insights from Genetic Absence Epilepsy Rats and Acute Pharmacological Model of Absence Seizures

Abstract

Introduction: Childhood Absence Epilepsy, a subtype of genetic generealised epilepsy, is characterised by sudden and brief episodes of impaired consciousness. The Leucine-rich glioma-inactivated protein 1 (LGI1) and N-methyl-D-aspartate receptor (NMDAR) are key proteins involved in regulating neuronal excitability. In conditions like anti-LGI1 encephalitis and anti-NMDAR encephalitis, autoantibodies target and disrupt these proteins, causing memory deficits, behavioural changes, sleep disturbances, and epileptic seizures. However, the roles of LGI1 and NMDAR dysfunction in the pathophysiology of absence of seizures remain unclear. This study aims to investigate the effects of LGI1 and NMDAR antibodies on absence seizures using two experimental models: Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and a low-dose pentylenetetrazol (PTZ) model of absence seizures. Methods: IgG purified from the peripheral blood of healthy controls (HC IgG), and patients with anti-NMDAR, and anti-LGI1 encephalitis, was administered intracerebroventricularly into GAERS and Wistar rats every other day for 11 days. Before and after antibody administration, electroencephalography (EEG) recordings were performed to analyse spontaneous spike-and-wave discharges (SWDs) in GAERS. In Wistar rats, after the completion of antibody infusions, PTZ was administered (35 mg/kg) on the 12 th day to induce absence seizures. The occurrence of PTZ-induced SWDs was quantified. Results: NMDAR IgG significantly increased the duration and number of SWDs in GAERS compared to HC IgG. LGI1 IgG had no significant effect, suggesting a differential role of NMDAR and LGI1 antibodies in modulating SWD activity. Similarly, NMDAR IgG-treated Wistar rats showed increased susceptibility to PTZ-induced absence seizures, while LGI1 IgG did not cause significant changes in PTZ-induced SWDs. Conclusion: These results reveal a distinct pro-epileptogenic effect of NMDAR antibodies in both genetic and pharmacological models of absence epilepsy, while LGI1 antibodies appear to have a negligible effect. These findings suggest a specific role for NMDAR dysfunction in absence seizure pathophysiology and support further investigation into antibody-mediated seizure mechanisms.