Increased seizure susceptibility in the collagen-induced arthritis mouse model depends on neuronal IL-1R1.

Aims: Numerous clinical studies have revealed a positive correlation between rheumatoid arthritis (RA) and an elevated risk of epilepsy. This study aimed to investigate the seizure susceptibility in the collagen-induced arthritis (CIA) mice model.

Main Methods: The classic CIA model was used to mimic RA pathogenesis in mice. The pentylenetetrazole (PTZ)-induced seizure model and audiogenic seizure model were used to evaluate seizure susceptibility. Neuroinflammation was assessed through ELISA, Western blot, and immunofluorescence staining. Additionally, electrophysiological techniques were applied to investigate the excitation/inhibition (E/I) balance.

Key Findings: CIA modeling raised the level of IL-1β, induced E/I imbalance in the dentate gyrus (DG) region, and enhanced seizure susceptibility to PTZ in C57BL/6 mice. However, knockout (KO) of IL-1β attenuated peripheral inflammatory symptoms and blocked the increase in seizure susceptibility in CIA-modeled mice. Additionally, conditional IL-1R1 KO in CaMKIIα-positive neurons did not affect the peripheral inflammatory symptoms but rescued both the increased seizure susceptibility and E/I imbalance in CIA-modeled mice. Furthermore, increased susceptibility to audiogenic seizure susceptibility was also observed in CIA-modeled BDA/1 mice, accompanied by the elevated IL-1β levels and neuronal IL-1R1-related Akt phosphorylation in the hippocampus.

Significance: Increased seizure susceptibility in the CIA mouse model depends on IL-1β and neuronal IL-1R1. These data indicated that IL-1β and neuronal IL-1R1 may be the key targets for its intervention.