Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mdx mice
Duchenne muscular dystrophy (DMD), an X-linked neuromuscular disorder, characterised by progressive immobility, chronic inflammation and premature death, is caused by the loss of the mechano-transducing signalling molecule, dystrophin. In non-contracting cells, such as neurons, dystrophin is likely...
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Elsevier
2025-02-01
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| Series: | Brain, Behavior, & Immunity - Health |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666354624002138 |
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| author | Kimberley A. Stephenson Aaron Barron Mark G. Rae Dervla O'Malley |
| author_facet | Kimberley A. Stephenson Aaron Barron Mark G. Rae Dervla O'Malley |
| author_sort | Kimberley A. Stephenson |
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| description | Duchenne muscular dystrophy (DMD), an X-linked neuromuscular disorder, characterised by progressive immobility, chronic inflammation and premature death, is caused by the loss of the mechano-transducing signalling molecule, dystrophin. In non-contracting cells, such as neurons, dystrophin is likely to have a functional role in synaptic plasticity, anchoring post-synaptic receptors. Dystrophin-expressing hippocampal neurons are key to cognitive functions such as emotions, learning and the consolidation of memories. In the context of disease-induced chronic inflammation, we have explored the role of the pleiotropic cytokine, interleukin (IL)-6 in hippocampal dysfunction using immunofluorescence, electrophysiology and metabolic measurements in dystrophic mdx mice. Hippocampal long-term potentiation (LTP) of the Schaffer collateral-CA1 projections was suppressed in mdx slices. Given the importance of mitochondria-generated ATP in synaptic plasticity, reduced maximal respiration in the CA1 region may impact upon this process. Consistent with a role for IL-6 in this observation, early LTP was suppressed in dystrophin-expressing wildtype slices exposed to IL-6. In dystrophic mdx mice, exposure to IL-6 suppressed mitochondrial-mediated basal metabolism in CA1, CA3 and DG hippocampal regions. Furthermore, blocking IL-6-mediated signalling by administering neutralising monoclonal IL-6 receptor antibodies intrathecally, normalised LTP in mdx mice. The impact of dystrophin loss from the hippocampus was associated with modified cellular bioenergetics, which underpin energy-driven processes such as the induction of LTP. The additional challenge of pathophysiological levels of IL-6 resulted in altered cellular bioenergetics, which may be key to cognitive deficits associated with the loss of dystrophin. |
| format | Article |
| id | doaj-art-830f15b1e31f40379e2575f5d7f381ce |
| institution | Kabale University |
| issn | 2666-3546 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Brain, Behavior, & Immunity - Health |
| spelling | doaj-art-830f15b1e31f40379e2575f5d7f381ce2025-01-26T05:05:03ZengElsevierBrain, Behavior, & Immunity - Health2666-35462025-02-0143100935Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mdx miceKimberley A. Stephenson0Aaron Barron1Mark G. Rae2Dervla O'Malley3Department of Physiology, School of Medicine, University College Cork, Western Road, Cork, IrelandDepartment of Anatomy and Neuroscience, University College Cork, Western Road, Cork, IrelandDepartment of Physiology, School of Medicine, University College Cork, Western Road, Cork, IrelandDepartment of Physiology, School of Medicine, University College Cork, Western Road, Cork, Ireland; APC Microbiome Ireland, University College Cork, Western Road, Cork, Ireland; Corresponding author. Department of Physiology, College of Medicine and Health, Western Gateway Building, University College Cork, Cork, Ireland.Duchenne muscular dystrophy (DMD), an X-linked neuromuscular disorder, characterised by progressive immobility, chronic inflammation and premature death, is caused by the loss of the mechano-transducing signalling molecule, dystrophin. In non-contracting cells, such as neurons, dystrophin is likely to have a functional role in synaptic plasticity, anchoring post-synaptic receptors. Dystrophin-expressing hippocampal neurons are key to cognitive functions such as emotions, learning and the consolidation of memories. In the context of disease-induced chronic inflammation, we have explored the role of the pleiotropic cytokine, interleukin (IL)-6 in hippocampal dysfunction using immunofluorescence, electrophysiology and metabolic measurements in dystrophic mdx mice. Hippocampal long-term potentiation (LTP) of the Schaffer collateral-CA1 projections was suppressed in mdx slices. Given the importance of mitochondria-generated ATP in synaptic plasticity, reduced maximal respiration in the CA1 region may impact upon this process. Consistent with a role for IL-6 in this observation, early LTP was suppressed in dystrophin-expressing wildtype slices exposed to IL-6. In dystrophic mdx mice, exposure to IL-6 suppressed mitochondrial-mediated basal metabolism in CA1, CA3 and DG hippocampal regions. Furthermore, blocking IL-6-mediated signalling by administering neutralising monoclonal IL-6 receptor antibodies intrathecally, normalised LTP in mdx mice. The impact of dystrophin loss from the hippocampus was associated with modified cellular bioenergetics, which underpin energy-driven processes such as the induction of LTP. The additional challenge of pathophysiological levels of IL-6 resulted in altered cellular bioenergetics, which may be key to cognitive deficits associated with the loss of dystrophin.http://www.sciencedirect.com/science/article/pii/S2666354624002138Duchenne muscular dystrophyDystrophinHippocampusInterleukin-6BioenergeticsLong-term potentiation |
| spellingShingle | Kimberley A. Stephenson Aaron Barron Mark G. Rae Dervla O'Malley Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mdx mice Brain, Behavior, & Immunity - Health Duchenne muscular dystrophy Dystrophin Hippocampus Interleukin-6 Bioenergetics Long-term potentiation |
| title | Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mdx mice |
| title_full | Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mdx mice |
| title_fullStr | Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mdx mice |
| title_full_unstemmed | Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mdx mice |
| title_short | Inhibition of hippocampal interleukin-6 receptor-evoked signalling normalises long-term potentiation in dystrophin-deficient mdx mice |
| title_sort | inhibition of hippocampal interleukin 6 receptor evoked signalling normalises long term potentiation in dystrophin deficient mdx mice |
| topic | Duchenne muscular dystrophy Dystrophin Hippocampus Interleukin-6 Bioenergetics Long-term potentiation |
| url | http://www.sciencedirect.com/science/article/pii/S2666354624002138 |
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