Work Package 3: Behavioural and neuropsychological phenotyping of dystrophic mouse models lacking different brain isoforms

Led by Cyrille Vaillend (CNRS)

Work package 3 of the BIND project is dedicated to the comparison of the cognitive and neuropsychiatric disorders expressed by various mouse models holding distinct mutations in the DMD gene and consequently deficiencies in different brain dystrophins. The behavioural studies of mice lacking only the full-length Dp427 dystrophin, or lacking both Dp427 and Dp140, and finally the mice lacking all dystrophins (i.e. Dp427, 140 and 71), have been distributed to 3 partners’ laboratories : Paris-Saclay Institute of Neuroscience (CNRS, France), Transpharmation Ireland Ltd. (TIL, Ireland) and Leiden University Medical Center (LUMC, The Netherlands). 

More than 28 tests have been performed in order to address many behavioural processes known to be affected in DMD: Motor coordination, depressive-like behaviour, social behaviour, anxiety, fear-related responses and learning, recognition memory, spatial learning, working memory and executive functions. We have addressed putative factors influencing phenotypes, such as the genetic background, hosting conditions, variations in testing protocols and test-retest procedures. We also have identified a range of phenotypes that are displayed in all mouse models, likely reflecting dysfunctions due to the loss of Dp427. Furthermore, we have also clarified the genotype-phenotype relationships associated with DMD, showing influence of mutation position on the severity of the deficits and identifying the selective impact of specific brain dystrophins. Interestingly, some of these phenotypes were subsequently identified in DMD patients, suggesting the importance of our multidisciplinary approach. 

This work allowed us to identify a range of behavioural and translational outcome measures that can be used as biomarkers to evaluate treatment effects. The robustness of these behavioural phenotypes has been evaluated, which will be useful for replication in other laboratories involved in preclinical studies of DMD brain comorbidities. Our results also provide new avenues for future studies to better understand the dysfunctional brain processes and circuits in both mouse models and DMD patients. Several publications of this work are in preparation.