The fatal X chromosome-linked disease, Duchenne muscular dystrophy (DMD) is a major health challenge for society. Caused by the loss of the sarcolemma-spanning structural protein dystrophin, which protects muscle cells from contraction-induced damage, the disease is characterised by inflammation and progressive physical disability, immobility and premature death. However, dystrophin is not only expressed in skeletal muscle but also in central neurons, with high levels of expression in the hippocampus, a brain region vital for learning and the acquisition of new memories. DMD sufferers often exhibit lower intelligence quotients and poor verbal working memory. Similarly, in dystrophin-deficient mdx mice, the pre-clinical model of DMD, there is evidence of loss or shrinkage of hippocampal neurons and deficits in recognition memory.
Levels of the pro-inflammatory cytokine, interleukin (IL)-6 are elevated in both DMD patients and mdx mice. IL-6 has known neuromodulatory effects on hippocampal neurons and modulates long term potentiation (LTP), the cellular correlate of memory formation. Given that peripheral levels of IL-6 are persistently elevated in DMD patients and mdx mice, IL-6 has been identified as a putative mediator of the cognitive deficits associated with dystrophin-deficiency. Thus, inhibiting central IL-6 signalling may improve memory consolidation and normalise aberrant hippocampal LTP in mdx mice. The proposed project will determine the role of IL-6 in learning and memory deficits using mdx mice by investigating neurotrophic effects of IL-6 on hippocampal neural network formation and synaptic plasticity. A pre-clinical in vivo intervention study, with behavioural assays, will be used to asses if recognition memory and aberrant hippocampal LTP are normalised by treatment with monoclonal IL-6 receptor antibodies. Consistent with the aims of the HRB research strategy, we anticipate that these studies will provide a better understanding of this illness and reveal a novel therapeutic target for improving the quality of life of DMD sufferers.
