Deficient Astrocyte Homeostatic Support Contributes to Brain Impairment in Duchenne Muscular Dystrophy

In addition to their muscle functions, dystrophins -the protein products of the DMD gene - also play a role in the central nervous system (CNS). In Duchenne muscular dystrophy (DMD), the progressive muscle degeneration, is associated with cognitive and behavioural impairments, which are severe in one-third of patients and substantially increase the overall clinical burden. The mechanisms of these neuropsychiatric abnormalities are complex and only partially understood. Specific dystrophins are functionally important in various brain cells and at their specialisations, with further diversity occurring throughout brain development and maturation across brain regions. Mutations affecting the full-length dystrophins (Dp427) cause the disease, while the additional loss of shorter isoforms (Dp140 and Dp71) can exacerbate the clinical presentation. Truncated dystrophins are strongly expressed in the healthy brain and therefore were investigated extensively, but most of DMD patients presenting with neuropsychiatric abnormalities do not have mutations affecting these isoforms. When the full-length dystrophins are considered, the abnormalities unquestionably involve not only neurones but also astrocytes, where absence of dystrophins reduces proliferation, disrupts neurotransmitter regulation, synaptic stability, and neurovascular integrity. Deficiency of astrocytic dystrophins impairs glutamate clearance, leading to excitotoxicity and neuronal hyperexcitability linked to multiple neuropsychiatric manifestations. This review evaluates evidence on dystrophin's role in astrocytes, its contribution to synaptic malfunction, and parallels with other neurodevelopmental disorders. Understanding that the deficient astrocyte homeostasis contributes to DMD can lead to the exploration of novel therapeutic strategies involving astrocyte-mediated neurotransmitter regulation to mitigate neuropsychiatric deficits.