Role of intracellular calcium stores in hair-cell ribbon synapse

Castellano-Muñoz, Manuel; Ricci, Anthony J.

doi:10.3389/fncel.2014.00162

Cited by 22 publications

(20 citation statements)

References 142 publications

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“…It is possible that noise-induced disruption of ER Ca 2+ dynamics may affect synaptic function; the ER is the primary store of intracellular Ca 2+ in presynaptic terminals, and Ca 2+ is a critical regulator of neurotransmitter release, hair-cell vesicle recruitment, and regulation and timing of vesicle fusion in ribbon synapses. 20 UPR-related modulation of Ca 2+ homeostasis alters synaptic transmission and plasticity, and ribbon synapse physiology depends on intracellular Ca 2+ buffering 21 .…”

Section: Discussionmentioning

confidence: 99%

Integrated Stress Response Inhibition Provides Sex-Dependent Protection Against Noise-Induced Cochlear Synaptopathy

Rouse

Matthews

Li³

et al. 2020

Preprint

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Noise-induced hearing loss (NIHL) is a common health concern with significant social, psychological, and cognitive implications. Moderate levels of acoustic overstimulation associated with tinnitus and impaired speech perception cause cochlear synaptopathy, characterized physiologically by reduction in wave I of the suprathreshold auditory brainstem response (ABR) and reduced number of synapses between sensory hair cells and auditory neurons. The unfolded protein response (UPR), an endoplasmic reticulum stress response pathway, has been implicated in the pathogenesis and treatment of NIHL as well as neurodegeneration and synaptic damage in the brain. In this study, we used the small molecule UPR modulator ISRIB (Integrated Stress Response InhiBitor) to treat noise-induced cochlear synaptopathy in a mouse model. Mice pretreated with ISRIB prior to noise-exposure were protected against noise-induced synapse loss. Male, but not female, mice also exhibited ISRIB-mediated protection against noise-induced suprathreshold ABR wave-I amplitude reduction. Female mice had higher baseline wave-I amplitudes but greater sensitivity to noise-induced wave-I reduction. Our results suggest that the UPR is implicated in noise-induced cochlear synaptopathy, and can be targeted for treatment.

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Section: Discussionmentioning

confidence: 99%

Integrated Stress Response Inhibition Provides Sex-Dependent Protection Against Noise-Induced Cochlear Synaptopathy

Rouse

Matthews

Li³

et al. 2020

Preprint

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“…Here it is well established that the unusual arrangement of vesicles in the ribbon and specialized proteins are required for fast docking and efficient exocytosis (40,41). Moreover, specific short-latency calcium channels have been suggested to be involved in allowing rapid vesicle release also in the ongoing response (42) as well as calcium-induced calcium release from specific internal stores (43). Such mechanisms are likely to also play a role in the central nervous system including the MNTB (44).…”

Section: Discussionmentioning

confidence: 99%

Input timing for spatial processing is precisely tuned via constant synaptic delays and myelination patterns in the auditory brainstem

Stange-Marten¹,

Nabel²,

Sinclair³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Precise timing of synaptic inputs is a fundamental principle of neural circuit processing. The temporal precision of postsynaptic input integration is known to vary with the computational requirements of a circuit, yet how the timing of action potentials is tuned presynaptically to match these processing demands is not well understood. In particular, action potential timing is shaped by the axonal conduction velocity and the duration of synaptic transmission delays within a pathway. However, it is not known to what extent these factors are adapted to the functional constraints of the respective circuit. Here, we report the finding of activity-invariant synaptic transmission delays as a functional adaptation for input timing adjustment in a brainstem sound localization circuit. We compared axonal and synaptic properties of the same pathway between two species with dissimilar timing requirements (gerbil and mouse): In gerbils (like humans), neuronal processing of sound source location requires exceptionally high input precision in the range of microseconds, but not in mice. Activityinvariant synaptic transmission and conduction delays were present exclusively in fast conducting axons of gerbils that also exhibited unusual structural adaptations in axon myelination for increased conduction velocity. In contrast, synaptic transmission delays in mice varied depending on activity levels, and axonal myelination and conduction velocity exhibited no adaptations. Thus, the specializations in gerbils and their absence in mice suggest an optimization of axonal and synaptic properties to the specific demands of sound localization. These findings significantly advance our understanding of structural and functional adaptations for circuit processing. myelination | synaptic transmission delay | sound localization | circuit processing | input timing T emporal integration of bioelectrical signals via chemical synapses is fundamental to neuronal computations. During circuit processing, neuronal information transfer via action potentials is controlled by exact differences in the occurrence between excitatory and inhibitory inputs (1-5). The arrival time of inputs within circuits in turn is largely shaped by the conduction delay of action potentials along the axons and during synaptic transmission. During ongoing activity, the transmission delays of chemical synapses generally increase in the range of hundreds of microseconds due to short-term adaptations (6-9). However, because temporal integration on postsynaptic neurons usually operates on time scales in the range of milliseconds or even longer (10, 11), sluggishness arising from synaptic mechanisms and axonal conductance is negligible for most of these computations. There are, however, some essential neuronal processing tasks that challenge the temporal precision of our nervous system. For instance, weakly electric fish detect miniature changes in the frequency of a constant electrical field. The neuronal circuits in these animals use electrical instead of chemical synapses in t...

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“…IHCs are connected to SG neurons by ribbon synapses,~16 ribbons per IHC. We next asked whether the maintenance of these ribbon synapses is affected by Manf inactivation, taking into account that ER stress is linked with changes in calcium dynamics and that the ribbon synapse physiology depends on intracellular calcium buffering 26 . We prepared whole mounts of cKO and control cochleas between 8 and 11 weeks of age and quantified the CtBP2-positive presynaptic ribbons per IHC.…”

Section: Conditional Inactivation Suggests a Local Function For Manf mentioning

confidence: 99%

Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss

et al. 2020

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The non-conventional neurotrophic factor mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that promotes ER homeostasis. MANF has a cytoprotective function, shown in the central nervous system neurons and pancreatic beta cells. Here, we report that MANF is expressed in the hair cells and neurons and in selected non-sensory cells of the cochlea and that Manf inactivation triggers upregulation of the ER chaperones in these cells. However, Manf inactivation resulted in the death of only outer hair cells (OHCs), the cells responsible for sound amplification in the cochlea. All OHCs were formed in Manf-inactivated mice, but progressive OHC death started soon after the onset of hearing function. The robust OHC loss was accompanied by strongly elevated hearing thresholds. Conditional Manf inactivation demonstrated that MANF has a local function in the cochlea. Immunostainings revealed the upregulation of CHOP, the pro-apoptotic component of the unfolded protein response (UPR), in Manf-inactivated OHCs, linking the UPR to the loss of these cells. The phenotype of Manf-inactivated OHCs was distinctly dependent on the mouse strain, such that the strains characterized by early-onset age-related hearing loss (C57BL/6J and CD-1) were affected. These results suggest that Manf deficiency becomes detrimental when accompanied by gene mutations that predispose to hearing loss, by intensifying ER dyshomeostasis. Together, MANF is the first growth factor shown to antagonize ER stress-mediated OHC death. MANF might serve as a therapeutic candidate for protection against hearing loss induced by the ER-machinery-targeting stressors.

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Role of intracellular calcium stores in hair-cell ribbon synapse

Cited by 22 publications

References 142 publications

Integrated Stress Response Inhibition Provides Sex-Dependent Protection Against Noise-Induced Cochlear Synaptopathy

Integrated Stress Response Inhibition Provides Sex-Dependent Protection Against Noise-Induced Cochlear Synaptopathy

Input timing for spatial processing is precisely tuned via constant synaptic delays and myelination patterns in the auditory brainstem

Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss

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