期刊
DISEASE MODELS & MECHANISMS
卷 13, 期 2, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.040840
关键词
Duchenne muscular dystrophy; mdx mice; Cerebellum; Purkinje cell; Cerebellar nuclei; Circuitry; In vivo electrophysiology
资金
- Baylor College of Medicine (BCM)
- Texas Children's Hospital
- Mrs. Clifford Elder White Graham Endowed Research Fund
- Hamill Foundation
- BCM IDDRC Project Development Award
- BCM IDDRC grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development [U54HD083092]
- National Center For Research Resources [C06RR029965]
- National Institute of Neurological Disorders and Stroke [R01 NS089664, R01 NS100874]
- Ruth L. Kirschstein National Research Service Award from the National Institute of Neurological Disorders and Stroke [F31 NS095491]
- National Ataxia Foundation (NAF)
Duchenne 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.
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