Cognitive dysfunction in the dystrophin-deficient mouse model of Duchenne muscular dystrophy: A reappraisal from sensory to executive processes

• Published in: Neurobiology of learning and memory 2015-10, Vol.124, p.111-122
• Main Authors: Chaussenot, Rémi, Edeline, Jean-Marc, Le Bec, Benoit, El Massioui, Nicole, Laroche, Serge, Vaillend, Cyrille
• Format: Article
• Language: English
• Subjects: Acoustic Stimulation; Animals; Associative learning; Auditory Perception - physiology; Avoidance Learning - physiology; Behavior, Animal - physiology; Brain - metabolism; Brain - physiopathology; Cognition Disorders - genetics; Cognition Disorders - physiopathology; Cognitive ability; Conditioning, Classical - physiology; Disease Models, Animal; Dystrophin - genetics; Dystrophin - metabolism; Evoked Potentials, Auditory, Brain Stem; Executive Function - physiology; Executive functions; Fear - physiology; Hearing; Language disorders; Learning; Life Sciences; Maze Learning - physiology; mdx mouse; Memory; Memory, Long-Term - physiology; Memory, Short-Term - physiology; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Muscular dystrophy; Muscular Dystrophy, Duchenne - genetics; Muscular Dystrophy, Duchenne - physiopathology; Muscular Dystrophy, Duchenne - psychology; Neurobiology; Neurons and Cognition; Reflex, Startle; Sensory Gating - physiology; Spatial learning; Spatial Memory - physiology; Spatial Navigation - physiology; Working memory
• ISSN: 1074-7427; 1095-9564
• DOI: 10.1016/j.nlm.2015.07.006

•Loss of brain full-length dystrophin alters cognitive function in muscular dystrophy.•We studied the role of brain dystrophin in sensory, learning and executive processes.•Dystrophin-deficient mdx mice show impaired amygdala-dependent fear learning.•Dystrophin plays a role in both acquisition and retention of associative memories.•Sensory processes, spatial working memory and cognitive flexibility are unaffected. Duchenne muscular dystrophy (DMD) is associated with language disabilities and deficits in learning and memory, leading to intellectual disability in a patient subpopulation. Recent studies suggest the presence of broader deficits affecting information processing, short-term memory and executive functions. While the absence of the full-length dystrophin (Dp427) is a common feature in all patients, variable mutation profiles may additionally alter distinct dystrophin-gene products encoded by separate promoters. However, the nature of the cognitive dysfunctions specifically associated with the loss of distinct brain dystrophins is unclear. Here we show that the loss of the full-length brain dystrophin in mdx mice does not modify the perception and sensorimotor gating of auditory inputs, as assessed using auditory brainstem recordings and prepulse inhibition of startle reflex. In contrast, both acquisition and long-term retention of cued and trace fear memories were impaired in mdx mice, suggesting alteration in a functional circuit including the amygdala. Spatial learning in the water maze revealed reduced path efficiency, suggesting qualitative alteration in mdx mice learning strategy. However, spatial working memory performance and cognitive flexibility challenged in various behavioral paradigms in water and radial-arm mazes were unimpaired. The full-length brain dystrophin therefore appears to play a role during acquisition of associative learning as well as in general processes involved in memory consolidation, but no overt involvement in working memory and/or executive functions could be demonstrated in spatial learning tasks.