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

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 hyperpolarizing responses upon activation of GABAARs. In addition, it is well-established that neuroinflammation 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 potentiates 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.

• Authors: Veronica Alfano, Alessia Romagnolo, James D Mills, Pierangelo Cifelli, Alessandro Gaeta, Alessandra Morano, Angelika Mühlebner, Eleonora Aronica, Eleonora Palma, Gabriele Ruffolo
• Journal: Brain sciences (Brain Sci) Vol. 12 Issue 6 (Jun 19 2022) ISSN: 2076-3425 [Print] Switzerland
• PMID: 35741692 (Publication Type: Journal Article)