GABAA currents are decreased by IL-1β in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis

• Published in: Neurobiology of disease Vol. 82; pp. 311 - 320
• Main Authors: Roseti, Cristina, van Vliet, Erwin A., Cifelli, Pierangelo, Ruffolo, Gabriele, Baayen, Johannes C., Di Castro, Maria Amalia, Bertollini, Cristina, Limatola, Cristina, Aronica, Eleonora, Vezzani, Annamaria, Palma, Eleonora
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2015; Elsevier
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Cerebral Cortex - pathology; Cerebral Cortex - physiopathology; Cerebral Cortex - surgery; Cytokine; Disease Models, Animal; Epilepsy, Temporal Lobe - pathology; Epilepsy, Temporal Lobe - physiopathology; Epilepsy, Temporal Lobe - surgery; Female; GABA Agents - administration & dosage; GABAA receptor; Hippocampus - pathology; Hippocampus - physiopathology; Hippocampus - surgery; Humans; Interleukin-1beta - administration & dosage; Interleukin-1beta - metabolism; Kainic Acid; Male; Middle Aged; Neuroinflammation; Neurology; Oocytes; Patch-Clamp Techniques; Pharmacoresistant epilepsy; Rats, Sprague-Dawley; Receptors, GABA-A - metabolism; Tissue Culture Techniques; Transplantation, Heterologous - methods; Xenopus; Young Adult; Interleukin-1 receptor-associated kinase1; Protein kinase C; IL-1 receptor type 1; IL-1 receptor antagonist; Interleukin-1β; Cytokine; Hippocampal sclerosis; Neuroinflammation; Oocytes; N-methyl-d-aspartate; Pharmacoresistant epilepsy; Gamma-aminobutyric acid; Temporal lobe epilepsy; GABA type A receptor; GABAA receptor; IL-1Ra; GABA A receptor; N-methyl- d-aspartate; HS; TLE; GABA A-R; IRAK1; NMDA; PKC; IL-1β; IL-1R1; GABA; GABA(A) receptor
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2015.07.003

Temporal lobe epilepsy (TLE) is the most prevalent form of adult focal onset epilepsy often associated with drug-resistant seizures. Numerous studies suggest that neuroinflammatory processes are pathologic hallmarks of both experimental and human epilepsy. In particular, the interleukin (IL)-1β/IL-1 receptor type 1 (R1) axis is activated in epileptogenic tissue, where it contributes significantly to the generation and recurrence of seizures in animal models. In this study, we investigated whether IL-1β affects the GABA-evoked currents (IGABA) in TLE tissue from humans. Given the limited availability of fresh human brain specimens, we used the “microtransplantation” method of injecting Xenopus oocytes with membranes from surgically resected hippocampal and cortical tissue from 21 patients with TLE and hippocampal sclerosis (HS), hippocampal tissue from five patients with TLE without HS, and autoptic and surgical brain specimens from 15 controls without epilepsy. We report the novel finding that pathophysiological concentrations of IL-1β decreased the IGABA amplitude by up to 30% in specimens from patients with TLE with or without HS, but not in control tissues. This effect was reproduced by patch-clamp recordings on neurons in entorhinal cortex slices from rats with chronic epilepsy, and was not observed in control slices. In TLE specimens from humans, the IL-1β effect was mediated by IL-1R1 and PKC. We also showed that IL-1R1 and IRAK1, the proximal kinase mediating the IL-1R1 signaling, are both up-regulated in the TLE compared with control specimens, thus supporting the idea that the IL-1β/IL-R1 axis is activated in human epilepsy. Our findings suggest a novel mechanism possibly underlying the ictogenic action of IL-1β, thus suggesting that this cytokine contributes to seizure generation in human TLE by reducing GABA-mediated neurotransmission. •Inflammatory IL-1β/IL1-R1/IRAK1 signaling is up-regulated in human cortical and hippocampal TLE tissue.•IL-1β decreases GABAA evoked currents in hippocampus and cortex from TLE but not controls.•IL-1β effect is mediated by IL-1R1 and PKC.•IL-1β may contribute to seizures in human TLE by reducing GABA-mediated neurotransmission.