title: GABAA currents are decreased by IL-1β in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis.
abstract: 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 (I(GABA)) 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 I(GABA) 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.
authors.affiliation: IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Roseti
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Erwin A
authors.initials: EA
authors.lastname: van Vliet
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, Rome, Italy; Ri.MED Foundation, Palermo, Italy.
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Cifelli
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, Rome, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Ruffolo
authors.affiliation: Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Baayen
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, Rome, Italy.
authors.forename: Maria Amalia
authors.initials: MA
authors.lastname: Di Castro
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bertollini
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, Rome, Italy; IRCCS Neuromed, Pozzilli, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Limatola
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center, University of Amsterdam, The Netherlands; Stichting Epilepsie Instellingen Nederland (SEIN-Heemstede), The Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy. Electronic address: annamaria.vezzani@marionegri.it.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
authors.affiliation: Department of Physiology and Pharmacology, Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome Sapienza, Rome, Italy; IRCCS San Raffaele Pisana, Rome, Italy. Electronic address: eleonora.palma@uniroma1.it.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Palma
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D005260:Female; D018682:GABA Agents / Q000008:administration & dosage; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D006801:Humans; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000378:metabolism*; D007608:Kainic Acid; D008297:Male; D008875:Middle Aged; D009865:Oocytes; D018408:Patch-Clamp Techniques; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014183:Transplantation, Heterologous / Q000379:methods; D014981:Xenopus; D055815:Young Adult
chemical_list: D018682:GABA Agents; D053583:Interleukin-1beta; D011963:Receptors, GABA-A; D007608:Kainic Acid
keywords: Cytokine; GABA(A) receptor; Neuroinflammation; Oocytes; Pharmacoresistant epilepsy