期刊
JOURNAL OF NEUROSCIENCE
卷 41, 期 2, 页码 376-389出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2142-20.2020
关键词
motor neuron death; neurodegeneration; neuronal activity; sensory-motor circuit; spinal muscular atrophy; synaptic dysfunction
资金
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [SI-1969/2-1]
- National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) [R01-NS078375]
- NIH Blueprint for Neuroscience Research
- National Institute on Alcohol Abuse and Alcoholism
- NINDS [R01-AA027079]
- SMA Foundation
- Project-ALS
The study reveals that chronic treatment with 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of spinal muscular atrophy (SMA) by increasing neuronal activity, restoring neurotransmission and synapse numbers, particularly proprioceptive synapses and neuromuscular junctions (NMJs), without affecting motor neuron death. Additionally, combining 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death leads to additive effects, fully correcting sensory-motor circuit pathology and enhancing phenotypic benefits in SMA mice.
Dysfunction of neuronal circuits is an important determinant of neurodegenerative diseases. Synaptic dysfunction, death, and intrinsic activity of neurons are thought to contribute to the demise of normal behavior in the disease state. However, the interplay between these major pathogenic events during disease progression is poorly understood. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the ubiquitously expressed protein SMN and is characterized by motor neuron death, skeletal muscle atrophy, as well as dysfunction and loss of both central and peripheral excitatory synapses. These disease hallmarks result in an overall reduction of neuronal activity in the spinal sensory-motor circuit. Here, we show that increasing neuronal activity by chronic treatment with the FDA-approved potassium channel blocker 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of SMA. 4-AP restores neurotransmission and number of proprioceptive synapses and neuromuscular junctions (NMJs), while having no effects on motor neuron death. In addition, 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death results in additive effects, leading to full correction of sensory-motor circuit pathology and enhanced phenotypic benefit in SMA mice. Our in vivo study reveals that 4-AP-induced increase of neuronal activity restores synaptic connectivity and function in the sensory-motor circuit to improve the SMA motor phenotype.
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