Résumé :
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Communication n° 620 Mutations affecting Dp71, major product of the dystrophin gene in the brain, are thought to be responsible for the most severe cases of mental retardation in DMD. To investigate this hypothesis, we evaluated the biochemical and behavioural consequences of a selective loss of Dp71 in KO-Dp71 mice. Using X-gal staining coupled with specific neuronal markers we found that Dp71-promoter activity may be detected in various brain cell types, including all neuronal cell types of the hippocampal formation, a brain structure largely involved in cognitive function. No gross anatomical alteration or neuronal loss was found in the KO-mice hippocampi. However, immunohistochemical analyses highlighted that the protein expression is mainly enriched in perivascular-astrocyte end-feet in adult brains. Immunostaining for Dp71, beta-dystroglycan, alpha-syntrophin and aquaporin channels was lost in perivascular astrocytes of the KO mice, indicating that this specific complex of Dp71-associated proteins collapses when Dp71 is lacking. To determine whether the loss of Dp71 and associated proteins affects cognitive functions, we compared the performance of KO-Dp71 mice and control littermates in a battery of behavioural tests assessing motor function, emotional reactivity, learning and memory. First, we showed that KO mice do not have major alterations of motor capabilities and exploratory activity. Preliminary results suggest that Dp71-null mice are not impaired in spatial delayed alternation behaviour and object recognition tests. Because deficits in such tests have been previously shown in the dystrophin-deficient mdx mice, our data suggest that alterations of long-term recognition memory are selectively due to altered expression of the full-length (Dp427) dystrophin. Experiments are currently undertaken to specify the nature and severity of the cognitive impairments displayed by KO-Dp71 mice in learning tasks involving distinct types of memory processes.
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