Emotional behavior and brain anatomy of the mdx52 mouse model of Duchenne muscular dystrophy

Abstract

The exon-52-deleted mdx52 mouse is a critical model of Duchenne muscular dystrophy (DMD), as it features a deletion in a hotspot region of the DMD gene, frequently mutated in patients. Deletion of exon 52 impedes expression of several brain dystrophins (Dp427, Dp260 and Dp140), thus providing a key model for studying the cognitive impairment associated with DMD and testing rescuing strategies. Here, using in vivo magnetic resonance imaging and neurohistology, we found no gross brain abnormalities in mdx52 mice, suggesting that the neural dysfunctions in this model are likely at the level of brain cellular functionalities. Then, we investigated emotional behavior and fear learning performance of mdx52 mice compared to mdx mice that only lack Dp427 to focus on behavioral phenotypes that could be used in future comparative preclinical studies. mdx52 mice displayed enhanced anxiety and a severe impairment in learning an amygdala-dependent Pavlovian association. These replicable behavioral outcome measures are reminiscent of the internalizing problems reported in a quarter of DMD patients, and will be useful for preclinical estimation of the efficacy of treatments targeting brain dysfunctions in DMD.

The BALB/c.mdx62 mouse exhibits a dystrophic muscle pathology and is a model of Duchenne muscular dystrophy

“…Loss of Dp260 and Dp140 could not be confirmed due to the inability to detect these isoforms in the brains of BALB/c WT mice, but it can be implied based on the locations of the promoters for these isoforms. There is potential for non-muscle phenotypes in these mice, such as those reported previously in mdx 52 mice ( Barboni et al, 2021 ; Saoudi et al, 2021 ). Importantly, this is the first mouse model with a mutation at exon 62.…”

Learning, memory and blood–brain barrier pathology in Duchenne muscular dystrophy mice lacking Dp427, or Dp427 and Dp140

“… 43 The decrease in alternation in our current study could indicate a partial deficit in working memory, however other factors, such as anxiety, could have influenced the alternation patterns. Mdx mice, and mice lacking Dp140 in addition, have increased anxiety, 23 , 26 , 28 , 43 which could have led to a preference for the previously explored areas. However, performance was consistent between trials, suggesting minimal involvement of habituation or stress due to repeated exposure.…”

“…Therefore, the lack of difference in anxiety in our study is most likely due to a suboptimal methodology, in which the lux of the lamp was probably too high, and does not directly contradict earlier research on increased anxiety in mice lacking Dp427 and Dp140. 28 …”

“…Deficits in fear‐learning, which is heavily dependent on the amygdala 47 have been studied before in mdx and mdx52 mice, lacking Dp427 and Dp140. 28 Spatial learning and spontaneous alterations are less dependent on amygdala involvement, but more on the hippocampus. 48 , 49 This suggests that learning and memory deficits caused by the lack of Dp140 are mostly dependent on the amygdala.…”

“…Both mouse models show deficits in cognitive processes such as fear and social behavior. 27 , 28 , 29 However, direct comparisons between mice lacking only Dp427 and mice lacking Dp427 + Dp140 are minimal, making it difficult to understand the exact effects of the lack of Dp140.…”