Duchenne muscular dystrophy (DMD) is a lethal X-linked disease characterized by muscular wasting due to lack of dystrophin (Dp427), a cytoskeletal protein expressed in muscle and selected brain regions (i.e. hippocampus). Dp427 binds to the Dystrophin Glycoprotein Complex (DGC) that spans the plasma membrane and modulates structural and several intracellular signaling properties (i.e. protein nytrosylation by neuronal nitric oxide synthase activation). The presence of the dystrophin-DGC in areas involved in motor, emotional and cognitive functions suggest that lack of Dp427 may be responsible for neurological disturbances described in DMD patients. These could be further aggravated by a condition of chronic stress, to which patients are subjected, and by cyclic therapeutic treatments with glucocorticoid (GC) for reducing muscular inflammation. Aim of the project is to uncover the effects that chronic treatment with GC and stress behavioral tests exert on brain regions susceptible to stressors and already compromised in DMD, as the hippocampus. In the first part of the study, we will perform a chronic treatment with GC of wild type (WT) and genetically dystrophic mdx mice, animal model of the pathology, in order to evaluate changes in hippocampal neurogenesis, a process highly stress-modulated. Moreover, as GC signaling is implicated in the pathogenesis of stress-related psychiatric disorders, i.e. post-traumatic disorder (PTSD), short and long term behavioral responses to a traumatic stress will be examined. Finally, since the lack of Dp427 has been linked with aberrant activity of histone deacetylases, due to an impaired nytrosylation, we will also analyze the global levels of histone acetylation in the hippocampus of both control and experimental WT and mdx mice. We expect to acquire information on the role of Dp427 in nervous system physiology, fundamental for prospecting therapeutic treatments for preventing or reducing, DMD-related neurological disorders.
