Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model
| Autor: | Virginie François, Ignacio Anegon, Mireille Ledevin, Caroline Le Guiner, Thibaut Larcher, D. Caudal, Corinne Huchet, A. Lafoux |
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| Přispěvatelé: | Therassay Platform, CAPACITES, Université de Nantes (UN), UMR1089, Nantes Gene Therapy Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM), Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, UMR 1064-CRTI, UMR 1089, Nantes Gene Therapy Laboratory, UMR 1089,Nantes Gene Therapy Laboratory, Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Expertise en Anatomie Pathologique (APEX), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ProdInra, Archive Ouverte, École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Central Nervous System
0301 basic medicine Sucrose Heredity Genetic Linkage Physiology Duchenne muscular dystrophy [SDV]Life Sciences [q-bio] Synaptogenesis Hippocampus Duchenne Muscular Dystrophy Anxiety Disaccharides Biochemistry Nervous System Muscular Dystrophies Dystrophin 0302 clinical medicine Medicine and Health Sciences Protein Isoforms Muscular dystrophy health care economics and organizations Mammals Multidisciplinary biology Organic Compounds Physics Eukaryota Classical Mechanics Brain Animal Models musculoskeletal system Phenotype [SDV] Life Sciences [q-bio] Chemistry medicine.anatomical_structure Experimental Organism Systems Neurology X-Linked Traits Sex Linkage Vertebrates Physical Sciences Mechanical Stress Medicine Anatomy Rats Transgenic Locomotion Research Article musculoskeletal diseases medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Transgene Science Central nervous system education Carbohydrates Research and Analysis Methods Rodents 03 medical and health sciences Model Organisms Internal medicine Genetics medicine Animals Maze Learning Muscle Skeletal Clinical Genetics Biological Locomotion Myocardium Organic Chemistry Organisms Chemical Compounds Biology and Life Sciences Proteins Muscular Dystrophy Animal medicine.disease Rats Cytoskeletal Proteins Thermal Stresses 030104 developmental biology Endocrinology Amniotes Animal Studies Mice Inbred mdx biology.protein Stress Psychological 030217 neurology & neurosurgery |
| Zdroj: | PLoS ONE PLoS ONE, Public Library of Science, 2020, 15 (3), pp.e0230083. ⟨10.1371/journal.pone.0230083⟩ PLoS ONE, Vol 15, Iss 3, p e0230083 (2020) Plos One 3 (15), e0230083. (2020) PLoS ONE, 2020, 15 (3), pp.e0230083. ⟨10.1371/journal.pone.0230083⟩ |
| ISSN: | 1932-6203 |
| Popis: | Duchenne Muscular Dystrophy (DMD) is a severe muscle-wasting disease caused by mutations in the DMD gene encoding dystrophin, expressed mainly in muscles but also in other tissues like retina and brain. Non-progressing cognitive dysfunction occurs in 20 to 50% of DMD patients. Furthermore, loss of expression of the Dp427 dystrophin isoform in the brain of mdx mice, the most used animal model of DMD, leads to behavioral deficits thought to be linked to insufficiencies in synaptogenesis and channel clustering at synapses. Mdx mice where the locomotor phenotype is mild also display a high and maladaptive response to stress. Recently, we generated Dmdmdx rats carrying an out-of frame mutation in exon 23 of the DMD gene and exhibiting a skeletal and cardiac muscle phenotype similar to DMD patients. In order to evaluate the impact of dystrophin loss on behavior, we explored locomotion parameters as well as anhedonia, anxiety and response to stress, in Dmdmdx rats aged from 1.5 to 7 months, in comparison to wild-type (WT) littermates. Pattern of dystrophin expression in the brain of WT and Dmdmdx rats was characterized by western-blot analyses and immunohistochemistry. We showed that dystrophin-deficient Dmdmdx rats displayed motor deficits in the beam test, without association with depressive or anxiety-like phenotype. However, Dmdmdx rats exhibited a strong response to restraint-induced stress, with a large increase in freezings frequency and duration, suggesting an alteration in a functional circuit including the amygdala. In brain, large dystrophin isoform Dp427 was not expressed in mutant animals. Dmdmdx rat is therefore a good animal model for preclinical evaluations of new treatments for DMD but care must be taken with their responses to mild stress. |
| Databáze: | OpenAIRE |
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