期刊
JOURNAL OF NEUROSCIENCE
卷 37, 期 15, 页码 4181-4199出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0282-16.2017
关键词
DFNA25; mutant mice VGLUT3(A224V/A224V); point mutation (p.A211V); STED; synaptic vesicles; vesicular glutamate transporter3 (VGLUT3)
资金
- Fondation pour la Recherche Medicale [Equipe FRM DEQ20130326486, FDT20140930909]
- Agence Nationale pour la Recherche
- Federation pour la Recherche sur le Cerveau
- Labex (Bio-Psy Laboratory of Excellence)
- Institut National de la Sante et de la Recherche Medicale (Inserm)
- CNRS
- Universite Pierre et Marie Curie (UPMC)
- Ministere de l'enseignement superieur et de la recherche
The atypical vesicular glutamate transporter type 3 (VGLUT3) is expressed by subpopulations of neurons using acetylcholine, GABA, or serotonin as neurotransmitters. In addition, VGLUT3 is expressed in the inner hair cells of the auditory system. A mutation (p. A211V) in the gene that encodes VGLUT3 is responsible for progressive deafness in two unrelated families. In this study, we investigated the consequences of the p. A211V mutation in cell cultures and in the CNS of a mutant mouse. The mutation substantially decreased VGLUT3 expression (-70%). Wemeasured VGLUT3-p.A211V activity by vesicular uptake in BON cells, electrophysiological recording of isolated neurons, and its ability to stimulate serotonergic accumulation in cortical synaptic vesicles. Despite a marked loss of expression, the activity of the mutated isoform was only minimally altered. Furthermore, mutant mice displayed none of the behavioral alterations that have previously been reported in VGLUT3 knock-out mice. Finally, we used stimulated emission depletion microscopy to analyze how the mutation altered VGLUT3 distribution within the terminals of mice expressing the mutated isoform. The mutation appeared to reduce the expression of theVGLUT3transporter by simultaneously decreasing the number of VGLUT3-positive synaptic vesicles and the amount of VGLUT3 per synapses. These observations suggested that VGLUT3 global activity is not linearly correlated with VGLUT3 expression. Furthermore, our data unraveled a nonuniform distribution of VGLUT3 in synaptic vesicles. Identifying the mechanisms responsible for this complex vesicular sorting will be critical to understand VGLUT's involvement in normal and pathological conditions.
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