Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses

Michalski, Nicolas; Goutman, Juan D.; Auclair, Sarah M.; Monvel, Jacques Boutet de; Tertrais, Margot; Emptoz, Alice; Parrin, Alexandre; Nouaille, Sylvie; Guillon, Marc; Sachse, Martin; Ćirić, Danica; Bahloul, Amel; Hardelin, Jean‐Pierre; Sutton, R. Bryan; Avan, Paul; Krishnakumar, Shyam S.; Rothman, James E.; Dulon, Didier; Safieddine, Saaïd; Petit, Christine

doi:10.7554/elife.31013

Cited by 99 publications

(128 citation statements)

References 91 publications

(163 reference statements)

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…Otoferlin plays an essential role in the late steps of IHC exocytosis, where it has been proposed to act as a priming factor and Ca 2+ sensor for exocytosis [59,99,[126][127][128][129]. This latter hypothesis is supported by the findings that at least four to five of otoferlin's C 2domains bind Ca 2+ and/or phospholipids [59,[130][131][132].…”

Section: Otoferlinmentioning

confidence: 96%

Balancing presynaptic release and endocytic membrane retrieval at hair cell ribbon synapses

Pangršič

Vogl

2018

FEBS Letters

View full text Add to dashboard Cite

The timely and reliable processing of auditory and vestibular information within the inner ear requires highly sophisticated sensory transduction pathways. On a cellular level, these demands are met by hair cells, which respond to sound waves – or alterations in body positioning – by releasing glutamate‐filled synaptic vesicles (SVs) from their presynaptic active zones with unprecedented speed and exquisite temporal fidelity, thereby initiating the auditory and vestibular pathways. In order to achieve this, hair cells have developed anatomical and molecular specializations, such as the characteristic and name‐giving ‘synaptic ribbons’ – presynaptically anchored dense bodies that tether SVs prior to release – as well as other unique or unconventional synaptic proteins. The tightly orchestrated interplay between these molecular components enables not only ultrafast exocytosis, but similarly rapid and efficient compensatory endocytosis. So far, the knowledge of how endocytosis operates at hair cell ribbon synapses is limited. In this Review, we summarize recent advances in our understanding of the SV cycle and molecular anatomy of hair cell ribbon synapses, with a focus on cochlear inner hair cells.

show abstract

Section: Otoferlinmentioning

confidence: 96%

Balancing presynaptic release and endocytic membrane retrieval at hair cell ribbon synapses

Pangršič

Vogl

2018

FEBS Letters

View full text Add to dashboard Cite

show abstract

“…I Ca TB is also absent in central synapses with non-compact conventional active zones, such as the calyx of Held synapse, although these synapses can release glutamate via fast Ca 2+ nanodomain-triggered exocytosis (Meinrenken et al, 2002; Nakamura et al, 2015). Furthermore, using otoferlin-knockout mice, we propose an additional role for this multi-C2 domain Ca 2+ sensor for exocytosis (Roux et al, 2006; Michalski et al, 2017); namely, otoferlin promotes a highly synchronous form of MVR at IHCs.…”

Section: Introductionmentioning

confidence: 96%

Clustered Ca2+ Channels Are Blocked by Synaptic Vesicle Proton Release at Mammalian Auditory Ribbon Synapses

et al. 2018

Self Cite

View full text Add to dashboard Cite

SUMMARY A Ca2+ current transient block (ICaTB) by protons occurs at some ribbon-type synapses after exocytosis, but this has not been observed at mammalian hair cells. Here we show that a robust ICaTB occurs at post-hearing mouse and gerbil inner hair cell (IHC) synapses, but not in immature IHC synapses, which contain non-compact active zones, where Ca2+ channels are loosely coupled to the release sites. Unlike ICaTB at other ribbon synapses, ICaTB in mammalian IHCs displays a surprising multi-peak structure that mirrors the EPSCs seen in paired recordings. Desynchronizing vesicular release with intracellular BAPTA or by deleting otoferlin, the Ca2+ sensor for exocytosis, greatly reduces ICaTB, whereas enhancing release synchronization by raising Ca2+ influx or temperature increases ICaTB. This suggests that ICaTB is produced by fast multivesicular proton-release events. We propose that ICaTB may function as a submillisecond feedback mechanism contributing to the auditory nerve’s fast spike adaptation during sound stimulation.

show abstract

“…; Michalski et al . ). Otoferlin is also involved in vesicle replenishment and re‐formation (Pangrsic et al .…”

Section: Introductionmentioning

confidence: 97%

“…, ; Michalski et al . ) and interacts with key synaptic proteins (Ramakrishnan et al . , ; Hams et al .…”

Section: Introductionmentioning

confidence: 99%

“…in cochlear inner hair cells (IHCs; Schug et al 2006;Pangrsic et al 2012;Ranum et al 2019). Instead of synaptotagmin I and II, which mediate transmitter release from CNS synapses, IHCs employ otoferlin as a Ca 2+ sensor, which is crucial for vesicle exocytosis from P4 onwards (Roux et al 2006;Beurg et al 2009;Heidrych et al 2009;Michalski et al 2017). Otoferlin is also involved in vesicle replenishment and re-formation (Pangrsic et al 2010;Duncker et al 2013;Vogl et al 2015Vogl et al , 2016Michalski et al 2017) and interacts with key synaptic proteins (Ramakrishnan et al 2009(Ramakrishnan et al , 2014Hams et al 2017).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Topographic map refinement and synaptic strengthening of a sound localization circuit require spontaneous peripheral activity

Müller

Sonntag

Maraslioglu

et al. 2019

The Journal of Physiology

View full text Add to dashboard Cite

Key points Loss of the calcium sensor otoferlin disrupts neurotransmission from inner hair cells. Central auditory nuclei are functionally denervated in otoferlin knockout mice (Otof KOs) via gene ablation confined to the periphery. We employed juvenile and young adult Otof KO mice (postnatal days (P)10–12 and P27–49) as a model for lacking spontaneous activity and deafness, respectively. We studied the impact of peripheral activity on synaptic refinement in the sound localization circuit from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO). MNTB in vivo recordings demonstrated drastically reduced spontaneous spiking and deafness in Otof KOs. Juvenile KOs showed impaired synapse elimination and strengthening, manifested by broader MNTB–LSO inputs, imprecise MNTB–LSO topography and weaker MNTB–LSO fibres. The impairments persisted into young adulthood. Further functional refinement after hearing onset was undetected in young adult wild‐types. Collectively, activity deprivation confined to peripheral protein loss impairs functional MNTB–LSO refinement during a critical prehearing period. Abstract Circuit refinement is critical for the developing sound localization pathways in the auditory brainstem. In prehearing mice (hearing onset around postnatal day (P)12), spontaneous activity propagates from the periphery to central auditory nuclei. At the glycinergic projection from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) of neonatal mice, super‐numerous MNTB fibres innervate a given LSO neuron. Between P4 and P9, MNTB fibres are functionally eliminated, whereas the remaining fibres are strengthened. Little is known about MNTB–LSO circuit refinement after P20. Moreover, MNTB–LSO refinement upon activity deprivation confined to the periphery is largely unexplored. This leaves a considerable knowledge gap, as deprivation often occurs in patients with congenital deafness, e.g. upon mutations in the otoferlin gene (OTOF). Here, we analysed juvenile (P10–12) and young adult (P27–49) otoferlin knockout (Otof KO) mice with respect to MNTB–LSO refinement. MNTB in vivo recordings revealed drastically reduced spontaneous activity and deafness in knockouts (KOs), confirming deprivation. As RNA sequencing revealed Otof absence in the MNTB and LSO of wild‐types, Otof loss in KOs is specific to the periphery. Functional denervation impaired MNTB–LSO synapse elimination and strengthening, which was assessed by glutamate uncaging and electrical stimulation. Impaired elimination led to imprecise MNTB–LSO topography. Impaired strengthening was associated with lower quantal content per MNTB fibre. In young adult KOs, the MNTB–LSO circuit remained unrefined. Further functional refinement after P12 appeared absent in wild‐types. Collectively, we provide novel insights into functional MNTB–LSO circuit maturation governed by a cochlea‐specific protein. The central malfunctions in Otof KOs may have implications for patients with sensorineuronal hearing loss.

show abstract

Otoferlin acts as a Ca2+ sensor for vesicle fusion and vesicle pool replenishment at auditory hair cell ribbon synapses

Cited by 99 publications

References 91 publications

Balancing presynaptic release and endocytic membrane retrieval at hair cell ribbon synapses

Balancing presynaptic release and endocytic membrane retrieval at hair cell ribbon synapses

Clustered Ca2+ Channels Are Blocked by Synaptic Vesicle Proton Release at Mammalian Auditory Ribbon Synapses

Topographic map refinement and synaptic strengthening of a sound localization circuit require spontaneous peripheral activity

Contact Info

Product

Resources

About