Cognitive flexibility deficits in a mouse model for the absence of full‐length dystrophin

Remmelink, Esther; Aartsma‐Rus, Annemieke; Smit, August B.; Verhage, Matthijs; Loos, Maarten; Putten, Maaike van

doi:10.1111/gbb.12301

Cited by 34 publications

(45 citation statements)

References 62 publications

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“…Indeed, in 2009 a group showed that this model did not display an anxiety-like phenotype in the elevated plus maze [24]. However, other recent studies indicate a deficit in the light-dark choice anxiety test [25,42]. Moreover, another group demonstrated anxiety-like and depression-like behaviors in mdx mice, associated with decreased BDNF (Brain derived neurotrophic factor) levels [43].…”

Section: Discussionmentioning

confidence: 99%

Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model

et al. 2020

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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 Dmd mdx 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 Dmd mdx 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 Dmd mdx rats was characterized by western-blot analyses and immunohistochemistry. We showed that dystrophin-deficient Dmd mdx rats displayed motor deficits in the beam test, without association with depressive or anxiety-like phenotype. However, Dmd mdx 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. Dmd mdx 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.

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Section: Discussionmentioning

confidence: 99%

Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model

et al. 2020

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“…The light↔dark transitions test was conducted as previously described to assess anxiety-like conflict behavior in mice. 21,22 Initially, mice were placed into the brightly lit compartment (~400 lux; 20×15×25 cm; facing away from the opening) and allowed to explore freely between the light and dark chambers (20×15×25 cm) for 10 min. The time spent in the light side chamber and the total transitions between the two sides of the chamber were automatically recorded using Noldus Observer software (Ethovision 11.0) and considered indices of anxiety and overall activity, respectively.…”

Section: Light↔dark Transitionsmentioning

confidence: 99%

Silica nanoparticle exposure during the neonatal period impairs hippocampal precursor proliferation and social behavior later in life

Gao

Gong

et al. 2018

IJN

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IntroductionSilica nanoparticles (SiO2-NPs) are currently among the most widely used nanomaterials, but their potentially adverse effects on brain development remain unknown. The developing brain is extremely sensitive to NP neurotoxicity during the early postnatal period.Materials and methodsHerein, we investigated the effects of SiO2-NPs (doses of 10, 20, or 50 mg with a particle size of ~91 nm, equivalent to aerosol mass concentrations 55.56, 111.11, and 277.78 mg/m3, respectively) exposure from postnatal day (P) 1 to P7 on hippocampal precursor proliferation at P8 and long-term neurobehavior in adults.ResultsSiO2-NP exposure resulted in inflammatory cell infiltration in lung tissue, microglia over-activation in the hippocampal dentate gyrus (DG), and decreased hippocampal precursor proliferation in the DG-subgranular zone at P8. Moreover, after exposure to 20 mg of SiO2-NPs, mice exhibited social interaction deficits and slight anxiety-like behaviors in adulthood, but this exposure did not induce locomotor activity impairment, depression-like behavior, or short-term memory impairment.DiscussionThese findings suggest that early-age SiO2-NP exposure induced inflammation and inhibited precursor proliferation in the DG in a dose-dependent manner, which might be related to the social dysfunction observed in adulthood.

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“…Similar to patients, absence of Dp427 in the mdx mouse is associated with behavioral and social impairments, such as enhanced freezing response in reaction to danger and altered ultrasonic vocal communication [ 31 – 33 ]. Learning and memory performance were also found to be impaired in some studies [ 34 – 37 ], though others report that spatial memory is largely unaffected [ 38 , 39 ]. Brain morphology of mdx mice has been reported in two studies [ 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

Influence of full-length dystrophin on brain volumes in mouse models of Duchenne muscular dystrophy

et al. 2018

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Duchenne muscular dystrophy (DMD) affects besides muscle also the brain, resulting in memory and behavioral problems. The consequences of dystrophinopathy on gross macroscopic alterations are unclear. To elucidate the effect of full-length dystrophin expression on brain morphology, we used high-resolution post-mortem MRI in mouse models that either express 0% (mdx), 100% (BL10) or a low amount of full-length dystrophin (mdx-XistΔhs). While absence or low amounts of full-length dystrophin did not significantly affect whole brain volume and skull morphology, we found differences in volume of individual brain structures. The results are in line with observations in humans, where whole brain volume was found to be reduced only in patients lacking both full-length dystrophin and the shorter isoform Dp140.

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Cognitive flexibility deficits in a mouse model for the absence of full‐length dystrophin

Cited by 34 publications

References 62 publications

Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model

Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model

Silica nanoparticle exposure during the neonatal period impairs hippocampal precursor proliferation and social behavior later in life

Influence of full-length dystrophin on brain volumes in mouse models of Duchenne muscular dystrophy

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