Dystrophic mdx mice are hypersensitive to acute and sub-chronic restraint stress: a behavioural and biochemical study

Duchenne Muscular Dystrophy (DMD) is a lethal neuromuscular disease caused by the lack of full-length dystrophin (Dp427), a cytoskeletal protein expressed in skeletal muscles, as well as in selected brain regions. In patients, as in mdx mice, an elective DMD animal model, lack of Dp427 severely affects the hippocampus, a brain region target of glucocorticoids (GCs) and important relay in stress responses. As chronic treatments with GCs are a golden standard in DMD therapy, it is conceivable that their persistent administration may further compromise hippocampal physiology. Our previous in vitro and in vivo studies have demonstrated that mdx mouse hippocampal neurons are significantly more sensitive, compared to wild-type, to both acute and sub-chronic administrations of GCs, highlighting a condition of hyper-responsiveness, characteristic of chronic stress responses. Aim of this study was to verify whether hippocampal neurons of the two genotypes respond differently also to induced stress conditions. Mice were subjected to either acute or sub-chronic tube-restraint stress, and several behavioural parameters were analysed by Elevated Plus Maze (EPM) and Open Field (OF) tests. In contrast to wild-type, mdx mice behaved similarly after both stress paradigms, not differentiating between acute and sub-chronic exposures. This was revealed by equally increased frequencies of entries in the open arms of the EPM, and higher distance covered and longer time spent in the periphery rather than in the center of the OF, with respect to their control. Accordingly, protein levels of hippocampal phosphorylated and total glucocorticoid receptors ratio (pGR/GR), used as an indicator of stress response, were significantly increased only in mdx mice after both acute and sub-chronic restraint procedures, suggesting inability in preventing GR hyperactivation in adverse situations. Overall, these results confirm a peculiar susceptibility of dystrophic hippocampal neurons to stress conditions and mediators, which on the long term could further impair their physiology.