期刊
JOURNAL OF NEUROSCIENCE
卷 39, 期 44, 页码 8798-8815出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1214-19.2019
关键词
amyotrophic lateral sclerosis; dynamic clamp; motor neurons; persistent sodium; proprioceptive neurons; SOD1
资金
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [NS095157]
- UCLA Faculty Research Grant
- National Institutes of Health/National Heart, Lung, and Blood Institute [1R01HL134346]
- David Vickter Foundation
- Toeffler Family & Simon-Strauss Foundation
- National Institutes of Health [R01CA196263]
- Knut and Alice Wallenberg Foundation
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons degenerate, resulting in muscle atrophy, paralysis, and fatality. Studies using mouse models of ALS indicate a protracted period of disease development with progressive motor neuron pathology, evident as early as embryonic and postnatal stages. Key missing information includes concomitant alterations in the sensorimotor circuit essential for normal development and function of the neuromuscular system. Leveraging unique brainstem circuitry, we show in vitro evidence for reflex circuit-specific postnatal abnormalities in the jaw proprioceptive sensory neurons in the well-studied SOD1(G)(93A) mouse. These include impaired and arrhythmic action potential burst discharge associated with a deficit in Nav 1.6 Na+ channels. However, the mechanoreceptive and nociceptive trigeminal ganglion neurons and the visual sensory retinal ganglion neurons were resistant to excitability changes in age-matched SOD1(G)(93A )mice. Computational modeling of the observed disruption in sensory patterns predicted asynchronous self-sustained motor neuron discharge suggestive of imminent reflexive defects, such as muscle fasciculations in ALS. These results demonstrate a novel reflex circuit-specific proprioceptive sensory abnormality in ALS.
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