Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model.
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 e...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2020-01-01
|
Series: | PLoS ONE |
Online Access: | https://doi.org/10.1371/journal.pone.0230083 |
id |
doaj-e779e72e0260449e94c985a27caf5ad5 |
---|---|
record_format |
Article |
spelling |
doaj-e779e72e0260449e94c985a27caf5ad52021-03-03T21:36:47ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01153e023008310.1371/journal.pone.0230083Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model.Dorian CaudalVirginie FrançoisAude LafouxMireille LedevinIgnacio AnegonCaroline Le GuinerThibaut LarcherCorinne HuchetDuchenne 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.https://doi.org/10.1371/journal.pone.0230083 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dorian Caudal Virginie François Aude Lafoux Mireille Ledevin Ignacio Anegon Caroline Le Guiner Thibaut Larcher Corinne Huchet |
spellingShingle |
Dorian Caudal Virginie François Aude Lafoux Mireille Ledevin Ignacio Anegon Caroline Le Guiner Thibaut Larcher Corinne Huchet Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model. PLoS ONE |
author_facet |
Dorian Caudal Virginie François Aude Lafoux Mireille Ledevin Ignacio Anegon Caroline Le Guiner Thibaut Larcher Corinne Huchet |
author_sort |
Dorian Caudal |
title |
Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model. |
title_short |
Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model. |
title_full |
Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model. |
title_fullStr |
Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model. |
title_full_unstemmed |
Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model. |
title_sort |
characterization of brain dystrophins absence and impact in dystrophin-deficient dmdmdx rat model. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2020-01-01 |
description |
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. |
url |
https://doi.org/10.1371/journal.pone.0230083 |
work_keys_str_mv |
AT doriancaudal characterizationofbraindystrophinsabsenceandimpactindystrophindeficientdmdmdxratmodel AT virginiefrancois characterizationofbraindystrophinsabsenceandimpactindystrophindeficientdmdmdxratmodel AT audelafoux characterizationofbraindystrophinsabsenceandimpactindystrophindeficientdmdmdxratmodel AT mireilleledevin characterizationofbraindystrophinsabsenceandimpactindystrophindeficientdmdmdxratmodel AT ignacioanegon characterizationofbraindystrophinsabsenceandimpactindystrophindeficientdmdmdxratmodel AT carolineleguiner characterizationofbraindystrophinsabsenceandimpactindystrophindeficientdmdmdxratmodel AT thibautlarcher characterizationofbraindystrophinsabsenceandimpactindystrophindeficientdmdmdxratmodel AT corinnehuchet characterizationofbraindystrophinsabsenceandimpactindystrophindeficientdmdmdxratmodel |
_version_ |
1714816084345880576 |