Myosin VI is required for the proper maturation and function of inner hair cell ribbon synapses

Inserm UMRS587, Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris cedex 15, France.
Human Molecular Genetics (Impact Factor: 6.39). 10/2009; 18(23):4615-28. DOI: 10.1093/hmg/ddp429
Source: PubMed


The ribbon synapses of auditory inner hair cells (IHCs) undergo morphological and electrophysiological transitions during
cochlear development. Here we report that myosin VI (Myo6), an actin-based motor protein involved in genetic forms of deafness,
is necessary for some of these changes to occur. By using post-embedding immunogold electron microscopy, we showed that Myo6
is present at the IHC synaptic active zone. In Snell's waltzer mutant mice, which lack Myo6, IHC ionic currents and ribbon
synapse maturation proceeded normally until at least post-natal day 6. In adult mutant mice, however, the IHCs displayed immature
potassium currents and still fired action potentials, as normally only observed in immature IHCs. In addition, the number
of ribbons per IHC was reduced by 30%, and 30% of the remaining ribbons were morphologically immature. Ca2+-dependent exocytosis probed by capacitance measurement was markedly reduced despite normal Ca2+ currents and the large proportion of morphologically mature synapses, which suggests additional defects, such as loose Ca2+-exocytosis coupling or inefficient vesicular supply. Finally, we provide evidence that Myo6 and otoferlin, a putative Ca2+ sensor of synaptic exocytosis also involved in a genetic form of deafness, interact at the IHC ribbon synapse, and we suggest
that this interaction is involved in the recycling of synaptic vesicles. Our findings thus uncover essential roles for Myo6
at the IHC ribbon synapse, in addition to that proposed in membrane turnover and anchoring at the apical surface of the hair

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Available from: Isabelle Roux
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    • "Please cite this article in press as: Yu, W.-M., Goodrich, L.V., Morphological and physiological development of auditory synapses, Hearing Research (2014), active zone and interacts with otoferlin (Heidrych et al., 2009; Roux et al., 2009). Myosin VI mutant IHCs fail to transport BK channels to the membrane and show immature exocytotic calcium efficiency and reduced ribbon number. "
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    ABSTRACT: Acoustic communication requires gathering, transforming, and interpreting diverse sound cues. To achieve this, all the spatial and temporal features of complex sound stimuli must be captured in the firing patterns of the primary sensory neurons and then accurately transmitted along auditory pathways for additional processing. The mammalian auditory system relies on several synapses with unique properties in order to meet this task: the auditory ribbon synapses, the endbulb of Held, and the calyx of Held. Each of these synapses develops morphological and electrophysiological characteristics that enable the remarkably precise signal transmission necessary for conveying the miniscule differences in timing that underly sound localization. In this article, we review the current knowledge of how these synapses develop and mature to acquire the specialized features necessary for the sense of hearing
    Full-text · Article · May 2014 · Hearing research
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    • "A.M.M. Oonk et al. / Hearing Research 299 (2013) 88e98 94 is reduced in mature IHC. In the absence of myosin VI, ribbon synapse maturation does not proceed normally and electrophysiological membrane properties of IHC remain immature (Roux et al., 2009). "
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    ABSTRACT: Since deafness is the most common sensorineural disorder in humans, better understanding of the underlying causes is necessary to improve counseling and rehabilitation. A Dutch family with autosomal dominantly inherited sensorineural hearing loss was clinically and genetically assessed. The MYO6 gene was selected to be sequenced because of similarities with other, previously described DFNA22 phenotypes and a pathogenic c.3610C>T (p.R1204W) mutation was found to co-segregate with the disease. This missense mutation results in a flat configured audiogram with a mild hearing loss, which becomes severe to profound and gently to steeply downsloping later in life. The age-related typical audiograms (ARTA) constructed for this family resemble presbyacusis. Speech audiometry and results of loudness scaling support the hypothesis that the phenotype of this specific MYO6 mutation mimics presbyacusis.
    Full-text · Article · Jan 2013 · Hearing research
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    • "From E16 on, while the differentiation of the auditory sensory epithelium proceeds from the cochlear base to its apex, the IHC synaptic machinery undergoes a series of morphofunctional changes ( Johnson et al. 2009, Kros 2007, Roux et al. 2009, Sobkowicz et al. 1986) (see Figure 2a). In the newborn mouse up to P6, the immature ribbons are typically electron dense spheres surrounded by synaptic vesicles (Roux et al. 2009, Sobkowicz et al. 1986). The postsynaptic density (PSD) appears later, at around P8 (Figure 2a), indicating that, as in CNS synapses, the presynaptic maturation precedes the postsynaptic one (Friedman et al. 2000). "
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    ABSTRACT: Cochlear inner hair cells (IHCs), the mammalian auditory sensory cells, encode acoustic signals with high fidelity by Graded variations of their membrane potential trigger rapid and sustained vesicle exocytosis at their ribbon synapses. The kinetics of glutamate release allows proper transfer of sound information to the primary afferent auditory neurons. Understanding the physiological properties and underlying molecular mechanisms of the IHC synaptic machinery, and especially its high temporal acuity, which is pivotal to speech perception, is a central issue of auditory science. During the past decade, substantial progress in high-resolution imaging and electrophysiological recordings, as well as the development of genetic approaches both in humans and in mice, has produced major insights regarding the morphological, physiological, and molecular characteristics of this synapse. Here we review this recent knowledge and discuss how it enlightens the way the IHC ribbon synapse develops and functions.
    Full-text · Article · Jul 2012 · Annual Review of Neuroscience
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