Unexpected Effect of IL-1β on the Function of GABAA Receptors in Pediatric Focal Cortical Dysplasia

Veronica Alfano, Alessia Romagnolo, James D. Mills, Pierangelo Cifelli, Alessandro Gaeta, Alessandra Morano, Angelika Mühlebner, Eleonora Aronica, Eleonora Palma, Gabriele Ruffolo

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Focal cortical dysplasia (FCD) type II is an epileptogenic malformation of the neocortex, as well as a leading cause of drug-resistant focal epilepsy in children and young adults. The synaptic dysfunctions leading to intractable seizures in this disease appear to have a tight relationship with the immaturity of GABAergic neurotransmission. The likely outcome would include hyperpolariz-ing responses upon activation of GABAARs. In addition, it is well-established that neuroinflamma-tion plays a relevant role in the pathogenesis of FCD type II. Here, we investigated whether IL-1β, a prototypical pro-inflammatory cytokine, can influence GABAergic neurotransmission in FCD brain tissues. To this purpose, we carried out electrophysiological recordings on Xenopus oocytes transplanted with human tissues and performed a transcriptomics analysis. We found that IL-1β decreases the GABA currents amplitude in tissue samples from adult individuals, while it potenti-ates GABA responses in samples from pediatric cases. Interestingly, these cases of pediatric FCD were characterized by a more depolarized EGABA and an altered transcriptomics profile, that revealed an up-regulation of chloride cotransporter NKCC1 and IL-1β. Altogether, these results suggest that the neuroinflammatory processes and altered chloride homeostasis can contribute together to increase the brain excitability underlying the occurrence of seizures in these children.
Original languageEnglish
Article number807
JournalBrain Sciences
Volume12
Issue number6
DOIs
Publication statusPublished - 1 Jun 2022

Keywords

  • FCD
  • GABAA current
  • IL-1β
  • human GABAA receptor

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