Synaptic transmission between end bulbs of Held and bushy cells in the cochlear nucleus of mice with a mutation in Otoferlin

Wright, Samantha; Hwang, Youngdeok; Oertel, Donata

doi:10.1152/jn.00522.2014

Cited by 28 publications

(29 citation statements)

References 98 publications

(89 reference statements)

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“…This suggests that otoferlin may play a developmental role and that the lack of otoferlin during a certain developmental window may have permanent effects on zebrafish physiology. In support of this, a recent study reported abnormally small ventral cochlear nuclei in otoferlin knockout mice (56). Future studies should focus on the developmental effects linked to otoferlin loss of function.…”

Section: Discussionmentioning

confidence: 63%

Otoferlin Deficiency in Zebrafish Results in Defects in Balance and Hearing: Rescue of the Balance and Hearing Phenotype with Full-Length and Truncated Forms of Mouse Otoferlin

Chatterjee

Padmanarayana

Abdullah

et al. 2015

Molecular and Cellular Biology

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Sensory hair cells convert mechanical motion into chemical signals.Otoferlin, a six-C2 domain transmembrane protein linked to deafness in humans, is hypothesized to play a role in exocytosis at hair cell ribbon synapses. To date, however, otoferlin has been studied almost exclusively in mouse models, and no rescue experiments have been reported. Here we describe the phenotype associated with morpholino-induced otoferlin knockdown in zebrafish and report the results of rescue experiments conducted with full-length and truncated forms of otoferlin. We found that expression of otoferlin occurs early in development and is restricted to hair cells and the midbrain. Immunofluorescence microscopy revealed localization to both apical and basolateral regions of hair cells. Knockdown of otoferlin resulted in hearing and balance defects, as well as locomotion deficiencies. Further, otoferlin morphants had uninflated swim bladders. Rescue experiments conducted with mouse otoferlin restored hearing, balance, and inflation of the swim bladder. Remarkably, truncated forms of otoferlin retaining the C-terminal C2F domain also rescued the otoferlin knockdown phenotype, while the individual N-terminal C2A domain did not. We conclude that otoferlin plays an evolutionarily conserved role in vertebrate hearing and that truncated forms of otoferlin can rescue hearing and balance.H air cells couple mechanical motion to neurotransmitter release at synapses (1). In contrast to conventional neural synapses, hair cell synapses release neurotransmitter continuously and, in a graded manner (2), possess synaptic ribbons (2-4), and lack synaptophysin (5), complexin (6-9), Munc13 (10), and the calcium sensors synaptotagmin I and II (11). In place of synaptotagmin, it is believed that otoferlin may confer calcium sensitivity to evoke neurotransmitter release (12, 13). Otoferlin is a six-C2 domain transmembrane protein expressed in inner, outer, and vestibular hair cells, as well as restricted regions of the brain (13-16). In humans, missense mutations in otoferlin have been linked to hearing loss (17,18), and biochemical studies have determined that otoferlin binds calcium and lipids (12,19), as well as membrane trafficking proteins (12,(20)(21)(22)(23). Further, in vitro assays have demonstrated that otoferlin accelerates SNARE-mediated membrane fusion (12). Based upon this evidence, it is hypothesized that otoferlin functions as a calcium-sensitive regulator of neurotransmitter release in sensory hair cells.However, the results of several studies have raised questions related to otoferlin's function. For instance, despite otoferlin expression in vestibular hair cells, knockout mice show no balance defects (24, 25) despite reduced exocytosis in vestibular type I hair cells (24,26). This raises questions as to the importance of otoferlin in this system. Further, otoferlin did not rescue synchronous neurotransmitter release in synaptotagmin I knockout cultured neurons, indicating that otoferlin and synaptotagmin are not functionally redundant (2...

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Section: Discussionmentioning

confidence: 63%

Otoferlin Deficiency in Zebrafish Results in Defects in Balance and Hearing: Rescue of the Balance and Hearing Phenotype with Full-Length and Truncated Forms of Mouse Otoferlin

Chatterjee

Padmanarayana

Abdullah

et al. 2015

Molecular and Cellular Biology

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“…), similar to the observation in the AVCN of Otof KOs (Wright et al . ). In contrast, eEPSCs at the calyx–MNTB synapse are normal in dn/dn mice (Oleskevich et al .…”

Section: Discussionmentioning

confidence: 97%

“…; Wright et al . ). The non‐functionality of otoferlin is due to a missense point mutation in the gene part encoding the C2B domain, one of six C2 domains in the 230 kDa protein.…”

Section: Introductionmentioning

confidence: 97%

“…Thus, humans with OTOF mutations (Petersen & Willems, 2006;Mahdieh et al 2012), as well as mutant Otof mice (Roux et al 2006;Longo-Guess et al 2007), generally suffer from defective transmission at IHC-auditory nerve fibre synapses (auditory synaptopathy; Starr & Rance, 2015;Moser & Starr, 2016). Auditory synaptopathy occurs in Otof deaf5/deaf5 mice, which are profoundly deaf as they lack auditory brainstem responses up to 100 dB sound pressure level (SPL) (Wilson et al 2005;Longo-Guess et al 2007;Wright et al 2014). The non-functionality of otoferlin is due to a missense point mutation in the gene part encoding the C2B domain, one of six C2 domains in the 230 kDa protein.…”

Section: Introductionmentioning

confidence: 99%

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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

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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.

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“…; Wright et al . ). During this critical period, the activity of endbulb of Held‐BC synapse can be enhanced by ATP (Dietz et al .…”

Section: Discussionmentioning

confidence: 97%

Tonotopic action potential tuning of maturing auditory neurons through endogenous ATP

Jovanovic

Radulović

Coddou

et al. 2016

The Journal of Physiology

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Synaptic refinement and strengthening are activity-dependent processes that establish orderly arranged cochleotopic maps throughout the central auditory system. The maturation of auditory brainstem circuits is guided by action potentials (APs) arising from the inner hair cells in the developing cochlea. The AP firing of developing central auditory neurons can be modulated by paracrine ATP signalling, as shown for the cochlear nucleus bushy cells and principal neurons in the medial nucleus of the trapezoid body. However, it is not clear whether neuronal activity may be specifically regulated with respect to the nuclear tonotopic position (i.e. sound frequency selectivity). Using slice recordings before hearing onset and in vivo recordings with iontophoretic drug applications after hearing onset, we show that cell-specific purinergic modulation follows a precise tonotopic pattern in the ventral cochlear nucleus of developing gerbils. In high-frequency regions, ATP responsiveness diminished before hearing onset. In low-to-mid frequency regions, ATP modulation persisted after hearing onset in a subset of low-frequency bushy cells (characteristic frequency< 10 kHz). Down-regulation of P2X2/3R currents along the tonotopic axis occurs simultaneously with an increase in AMPA receptor currents, thus suggesting a high-to-low frequency maturation pattern. Facilitated AP generation, measured as higher firing frequency, shorter EPSP-AP delay in vivo, and shorter AP latency in slice experiments, is consistent with increased synaptic efficacy caused by ATP. Finally, by combining recordings and pharmacology in vivo, in slices, and in human embryonic kidney 293 cells, it was shown that the long lasting change in intrinsic neuronal excitability is mediated by the P2X2/3R.

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Synaptic transmission between end bulbs of Held and bushy cells in the cochlear nucleus of mice with a mutation in Otoferlin

Cited by 28 publications

References 98 publications

Otoferlin Deficiency in Zebrafish Results in Defects in Balance and Hearing: Rescue of the Balance and Hearing Phenotype with Full-Length and Truncated Forms of Mouse Otoferlin

Otoferlin Deficiency in Zebrafish Results in Defects in Balance and Hearing: Rescue of the Balance and Hearing Phenotype with Full-Length and Truncated Forms of Mouse Otoferlin

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

Tonotopic action potential tuning of maturing auditory neurons through endogenous ATP

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