Abstract
ABSTRACTDuchenne muscular dystrophy (DMD) is a debilitating and ultimately lethal disease involving progressive muscle degeneration and neurological dysfunction. DMD is caused by mutations in the dystrophin gene, which result in extremely low or total loss of dystrophin protein expression. In the brain, dystrophin is heavily localized to cerebellar Purkinje cells, which control motor and non-motor functions. In vitro experiments in mouse Purkinje cells revealed that loss of dystrophin leads to low firing rates and high spiking variability. However, it is still unclear how the loss of dystrophin affects cerebellar function in the intact brain. Here, we used in vivo electrophysiology to record Purkinje cells and cerebellar nuclear neurons in awake and anesthetized female mdx (also known as Dmd) mice. Purkinje cell simple spike firing rate is significantly lower in mdx mice compared to controls. Although simple spike firing regularity is not affected, complex spike regularity is increased in mdx mutants. Mean firing rate in cerebellar nuclear neurons is not altered in mdx mice, but their local firing pattern is irregular. Based on the relatively well-preserved cytoarchitecture in the mdx cerebellum, our data suggest that faulty signals across the circuit between Purkinje cells and cerebellar nuclei drive the abnormal firing activity. The in vivo requirements of dystrophin during cerebellar circuit communication could help explain the motor and cognitive anomalies seen in individuals with DMD.This article has an associated First Person interview with the first author of the paper.
Highlights
Duchenne muscular dystrophy (DMD) is a devastating X-linked disease that affects ~1 in 5,000 boys (Guiraud et al, 2015)
Our experiments revealed three main findings: 1) Purkinje cell simple spike firing rate is significantly lower in mdx mutant mice; 2) the pattern of firing in mdx cerebellar nuclear neurons is more irregular compared to controls; and 3) the overall firing features of the mdx Purkinje cells are highly reminiscent of the defects observed in several mutant mouse strains that model cerebellar disease, including ataxia and dystonia (Fremont et al, 2014; Gao et al, 2012; White and Sillitoe, 2017; White et al, 2014; White et al, 2016a)
Boys are affected in the severe forms, which start with muscle degeneration, cardiac and respiratory problems often determine the end-point of the disease
Summary
Duchenne muscular dystrophy (DMD) is a devastating X-linked disease that affects ~1 in 5,000 boys (Guiraud et al, 2015). DMD mutations cause the milder disease, Becker muscular dystrophy (BMD), as well as X-linked dilated cardiomyopathy (XLDC). Heterozygous female carriers of DMD mutations are typically asymptomatic, up to approximately 8% of these carriers are considered as manifesting carriers who develop symptoms ranging from mild muscle weakness to a rapidly progressive DMD-like muscular dystrophy (Birnkrant et al, 2018; Moser and Emery, 1974; Norman and Harper, 1989; Taylor et al, 2007). We used an mdx mouse model to test how the loss of dystrophin (Dp427 isoform) alters cerebellar function by measuring neuronal activity in vivo (Grady et al, 2006; Ryder-Cook et al, 1988; Sicinski et al, 1989; Sillitoe et al, 2003)
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