X-linked Duchenne muscular dystrophy (DMD), caused by mutations in a gene coding several dystrophin isoforms from independent promoters, is associated with a range of brain-related comorbidities. Intellectual disability is variably expressed depending on the position of the genetic variants, intelligence quotients being negatively correlated with the number of deficient brain dystrophins. However, the genetic basis of other phenotypes underlying cognitive deficits and neuropsychiatric disorders, such as executive dysfunctions and attention deficit/hyperactivity disorder (ADHD), is still unclear. In this study, we behaviourally characterized two mouse models (mdx5Cv, mdx52) lacking brain dystrophins, Dp427 or Dp427 and Dp140 respectively, which together correspond to about 90% of DMD patients' mutation profiles. We included new paradigms allowing automated, high-throughput, collection of behavioural data from social groups of mice in home-cage conditions. We show that both models display unaltered circadian exploratory activity in such conditions, opposite of the motor inhibition expressed in stand-alone behavioural tests. In contrast, both models variably developed hyperactivity, impulsive and perseverative behaviours, triggered by sudden task-condition changes such as increases in waiting delays to access rewards, with a moderate impact on delay discounting. Cumulative Dp427 and Dp140 deficiency resulted in reduced memory of fear extinction and impaired behavioural flexibility during reversal of the learning-strategy rule in a working-memory task. These results are relevant to the comorbid diagnosis of ADHD across main mutation profiles in DMD; they also highlight a specific contribution of Dp140 deficiency to maladaptive behavioural inflexibility, and provide new genotype-specific outcome measures to probe brain-targeting treatments in future preclinical studies.
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