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2045-23221512025May30Scientific reportsSci RepNeuronal hyperexcitability in dystrophin-deficient mdx hippocampal neurons: the importance of interleukin-6 and GABAergic regulation.18984189841898410.1038/s41598-025-00880-zDuchenne Muscular Dystrophy (DMD) is a severe neuromuscular disorder arising from loss of the structural protein, dystrophin. It also often presents with cognitive deficits and susceptibility to epilepsy. Expressed in neurons of the hippocampus, dystrophin plays an important role in synapse formation, specifically the post-synaptic organisation of γ-aminobutyric acid A receptors (GABAARs). This study explored possible interactions between interleukin (IL)-6, which is elevated in DMD, and GABAAR signalling in cultured hippocampal neurons of dystrophic mdx mice. Immunofluorescent imaging revealed altered development of network connectivity that displayed similar characteristics to dystrophin-expressing neurons cultured in elevated levels of IL-6. Mdx neurons dependably exhibited spontaneous oscillations. Calcium (Ca2+) signalling was further modulated by exposure to agonists and antagonists of GABAA and GABABRs. IL-6-evoked Ca2+ responses were enhanced by muscimol, a GABAAR agonist, in wildtype (WT) and mdx neurons, whilst bicuculline, a GABAAR antagonist, only suppressed IL-6-evoked Ca2+activity in WT neurons. The GABABR agonist, baclofen, enhanced IL-6-evoked Ca2+ responses only in mdx neurons. Our findings support dysfunctional GABAergic signalling in hippocampal neurons that lack dystrophin, resulting in aberrant neuronal network excitability. The contribution of elevated levels of IL-6 further impact upon Ca2+ dyshomeostasis in dystrophic neurons and may underpin cognitive changes reported in dystrophinopathies.© 2025. The Author(s).StephensonKimberley AKADepartment of Physiology, School of Medicine, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.XiaoQiaoQDepartment of Physiology, School of Medicine, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.VaughanMichael BMBDepartment of Physiology, School of Medicine, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.PetersPollyPDepartment of Physiology, School of Medicine, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.DenleyClaireCDepartment of Physiology, School of Medicine, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.O'MearaSeanSDepartment of Physiology, School of Medicine, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.SheehanCeceliaCDepartment of Physiology, School of Medicine, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.RaeMark GMGDepartment of Physiology, School of Medicine, University College Cork, Western Gateway Building, Western Road, Cork, Ireland.O'MalleyDervlaD0000-0002-7031-4879Department of Physiology, School of Medicine, University College Cork, Western Gateway Building, Western Road, Cork, Ireland. d.omalley@ucc.ie.engILP-POR-2017-040HRBI_Health Research BoardIrelandJournal Article20250530
EnglandSci Rep1015632882045-23220Interleukin-60Dystrophin0Receptors, GABA-ASY7Q814VUPCalcium56-12-2gamma-Aminobutyric AcidIMAnimalsHippocampusmetabolismpathologycytologyInterleukin-6metabolismDystrophindeficiencygeneticsmetabolismMice, Inbred mdxNeuronsmetabolismdrug effectsMiceMuscular Dystrophy, DuchennemetabolismgeneticsReceptors, GABA-AmetabolismCalcium Signalingdrug effectsCells, CulturedCalciummetabolismgamma-Aminobutyric AcidmetabolismMice, Inbred C57BLDuchenne muscular dystrophyDystrophinGABAHippocampusLearningMemoryDeclarations. Competing interests: The authors declare no competing interests. Ethics approval: All animal experiments were approved and performed following guidelines set out by the HPRA (Health Products Regulatory Authority), Ireland and following project authorisation (AEI9130/P088), as well as individual authorisation (AEI9130/I303). 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