Investigating the role of interleukin-6 in neuronal dysfunction in the mdx mouse model of Duchenne muscular dystrophy

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Stephenson, Kimberley Alix
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University College Cork
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Duchenne Muscular Dystrophy (DMD) is a fatal musculoskeletal disorder that results in a loss of dystrophin in muscle fibres, leading to progressive immobility, chronic inflammation and premature death. Inflammation is characterised by increased circulating levels of pro-inflammatory cytokines such as IL-6. However, it is apparent that dystrophin not only functions in skeletal muscle, but in the CNS as well, with an increased incidence of cognitive impairment and deficits in verbal, short-term and working memory in individuals with DMD. The hippocampus is critical for learning and the formation and consolidation of memories and can be modified by neuroimmune cytokines, such as IL-6. The aim of this programme of research was to investigate the possible contribution of the neuroimmune molecule, IL-6 in cognitive impairment associated with loss of the structural protein, dystrophin. Initially, we used the dystrophic mdx mouse to investigate what impact loss of dystrophin had on normal hippocampal function. Significantly, LTP, the molecular correlate of learning and memory was shown to be decreased in mdx mice, which has been linked to memory dysfunction. Moreover, changes in the density and structure of mdx hippocampal neurons and glia was observed over time. Subsequently, we examined the possible effects of IL-6 on hippocampal function in mdx mice. IL-6 and IL-6R expression were altered in specific regions in the hippocampus, which underpins function relating to learning and memory. Indeed, in vivo blockade of IL-6-mediated signalling in the CNS of mdx mice restored LTP, although at this age, it did not impact on learning behaviours. These studies have elucidated previously unknown cellular and molecular changes in the hippocampus of dystrophin-deficient mice. Moreover, we have linked the neuromodulatory cytokine, IL-6, with the observed pathophysiology.
DMD , IL-6 , LTP , Cognitive impairment
Stephenson, K. A. 2022. Investigating the role of interleukin-6 in neuronal dysfunction in the mdx mouse model of Duchenne muscular dystrophy. PhD Thesis, University College Cork.