Cognitive dysfunction in Duchenne muscular dystrophy: a possible role for neuromodulatory immune molecules

Mark G Rae, Dervla O'Malley

Duchenne Muscular Dystrophy (DMD) is an X chromosome-linked disease characterized by progressive physical disability, immobility and premature death in affected boys. Underlying the devastating symptoms of DMD is the loss of dystrophin, a structural protein which connects the extracellular matrix to the cell cytoskeleton and provides protection against contraction-induced damage in muscle cells, leading to chronic peripheral inflammation. However, dystrophin is also expressed in neurons within specific brain regions, including the hippocampus, a structure associated with learning and memory formation. Linked to this, a subset of boys with DMD exhibit non-progressing cognitive dysfunction, with deficits in verbal, short-term and working memory. Furthermore, in the genetically comparable dystrophin-deficient mdx mouse model of DMD, some, but not all, types of learning and memory are deficient and specific deficits in synaptogenesis and channel clustering at synapses has been noted. Little consideration has been devoted to the cognitive deficits associated with DMD in comparison to the research conducted into the peripheral effects of dystrophin deficiency. Therefore, this review will focus upon what is known about the role of full length dystrophin (Dp427) in hippocampal neurons. The importance of dystrophin in learning and memory will be assessed and the potential importance that inflammatory mediators, which are chronically elevated in dystrophinopathies, may have on hippocampal function will also be evaluated.