BEHAVIOURAL ABNORMALITIES IN DMSXL MICE, A MODEL OF MYOTONIC DYSTROPHY TYPE 1

Myotonic dystrophy type 1 (DM1) is a dominantly inherited neuromuscular disease caused by the abnormal expansion of CTG-repeats in the 3'-untranslated region of the DMPK gene, characterized by multisystemic symptoms including muscle weakness, myotonia, cardio-respiratory problems, hypersomnia, cognitive dysfunction and behavioural abnormalities. DMSXL mice carry a mutated human DMPK transgene resulting in >1000 CTG-repeats. They exhibit a pathologic neuromuscular phenotype and also synaptic dysfunction resulting in neurological and behavioural deficits similar to those observed in patients. To further explore additional phenotypes of this DM1 mouse model we developed a comprehensive battery of tests that included the evaluation of several brain functions: exploratory and motor activity, fine motor skills, neuromuscular strength, anxiety, working memory, fear learning, sensorimotor processing, spatial memory, home-cage rest behaviour. Additionally, skeletal and cranio-facial morphology as well as body composition and bone mineral density were assessed using DEXA and micro-CT. Male and female DMSXL mice tested between 7 and 20 weeks of age showed, compared to wildtype littermates: lower body weight, reduced grip strength and running wheel activity and increased anxiety, consistently with previously published data. Interestingly, they also presented some new phenotypes remarkably similar to the characteristic features of the human disease: skeletal and cranio-facial dysmorphology with teeth misalignment, abnormalities in sensorimotor processing and rest-related disturbances during the active phase. These phenotypes confirm the reliability of DMSXL mice to model clinical features of DM1 and open new opportunities to verify the efficacy of novel therapies based on CRISPR/Cas9-mediated gene editing strategies currently under study in our group.