The neurological and behavioral consequences of dystrophin deficiency in Duchenne muscular dystrophy: insights from mouse models

Verhaeg, M.A.T.

Duchenne muscular dystrophy (DMD) is a severe, progressive disorder, caused by mutations in the DMD gene that disrupt dystrophin production. These mutations leads to muscle degeneration and, in some cases, cognitive and behavioral issues such as autism, ADHD, anxiety, and learning disabilities. From the different dystrophin isoforms, Dp427, Dp140, Dp71, and Dp40 are normally present in the brain, and loss of specific isoforms in DMD is linked to neurological symptoms. Animal models have been essential for understanding DMD and developing treatments. However, the behavioral and neurological deficits are underexplored, especially in models missing multiple dystrophin isoforms. In this thesis, the lack of Dp427 is correlated to deficits in working memory, anxiety, and blood-brain barrier integrity, while the absence of Dp140 and Dp71/Dp40 can further exacerbate behavioral symptoms, especially anxiety and fear reactivity. Short-term corticosteroid treatment had minimal negative...Show moreDuchenne muscular dystrophy (DMD) is a severe, progressive disorder, caused by mutations in the DMD gene that disrupt dystrophin production. These mutations leads to muscle degeneration and, in some cases, cognitive and behavioral issues such as autism, ADHD, anxiety, and learning disabilities. From the different dystrophin isoforms, Dp427, Dp140, Dp71, and Dp40 are normally present in the brain, and loss of specific isoforms in DMD is linked to neurological symptoms. Animal models have been essential for understanding DMD and developing treatments. However, the behavioral and neurological deficits are underexplored, especially in models missing multiple dystrophin isoforms. In this thesis, the lack of Dp427 is correlated to deficits in working memory, anxiety, and blood-brain barrier integrity, while the absence of Dp140 and Dp71/Dp40 can further exacerbate behavioral symptoms, especially anxiety and fear reactivity. Short-term corticosteroid treatment had minimal negative impact on cognition, though long-term effects remain unclear. Brain imaging studies revealed reduced cerebral perfusion and disrupted AQP4 organization in mice lacking all isoforms. These findings underscore the complexity of DMD and the importance of addressing both muscular and neurological aspects of the disease. Multidisciplinary research and inclusion of brain-targeted therapies are crucial for improving quality of life for individuals with DMD.
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The neurological and behavioral consequences of dystrophin deficiency in Duchenne muscular dystrophy: insights from mouse models