期刊
MOLECULAR AND CELLULAR NEUROSCIENCE
卷 88, 期 -, 页码 308-318出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mcn.2018.03.006
关键词
24S-hydroxycholesterol; Amyotrophic lateral sclerosis; Neuromuscular junction; Synaptic vesicle; Exocytosis; Nitric oxide; Lipid rafts
资金
- RFBR [17-04-00046]
- RSF [14-15-00847]
- program for support of bioresource collections of FASO
- Russian Science Foundation [17-15-00070] Funding Source: Russian Science Foundation
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the initial denervation of skeletal muscle and subsequent death of motor neurons. A dying-back pattern of ALS suggests a crucial role for neuromuscular junction dysfunction. In the present study, microelectrode recording of postsynaptic currents and optical detection of synaptic vesicle traffic (FM1-43 dye) and intracellular NO levels (DAF-FM DA) were used to examine the effect of the major brain-derived cholesterol metabolite 24S-hydroxycholesterol (24S-HC, 0.4 mu M) on neuromuscular transmission in the diaphragm of transgenic mice carrying a mutant superoxide dismutase 1 (SODG93A). We found that 24S-HC suppressed spontaneous neurotransmitter release and neurotransmitter exocytosis during high-frequency stimulation. The latter was accompanied by a decrease in both the rate of synaptic vesicle recycling and activity-dependent enhancement of NO production. Inhibition of NO synthase with L-NAME also attenuated synaptic vesicle exocytosis during high-frequency stimulation and completely abolished the effect of 24S-HC itself. Of note, 24S-HC enhanced the labeling of synaptic membranes with B subunit of cholera toxin, suggesting an increase in lipid ordering. Lipid raft-disrupting agents (methyl-P-cyclodextrin, sphingomyelinase) prevented the action of 24S-HC on both lipid raft marker labeling and NO synthesis. Together, these experiments indicate that 24S-HC is able to suppress the exocytotic release of neurotransmitter in response to intense activity via a NO/lipid raft-dependent pathway in the neuromuscular junctions of SODG93A mice.
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