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Piccolino is required for ribbon architecture at cochlear inner hair cell synapses and for hearing

ABSTRACT: Cochlear inner hair cells (IHCs) form specialized ribbon synapses with spiral ganglion neurons that tirelessly transmit sound information at high rates over long time periods with extreme temporal precision. This functional specialization is essential for sound encoding and is attributed to a distinct molecular machinery with unique players or splice variants compared to conventional neuronal synapses. Among these is the active zone (AZ) scaffold protein piccolo/aczonin, which is represented by its short splice variant piccolino at cochlear and retinal ribbon synapses. While the function of piccolo at synapses of the central nervous system has been intensively investigated, the role of piccolino at IHC synapses remains unclear. In this study, we characterize the structure and function of IHC-synapses in piccolo gene-trap mutant rats (Pclogt/gt). We find a mild hearing deficit with elevated thresholds and reduced amplitudes of auditory brainstem responses. Ca2+ channel distribution and ribbon morphology are altered in apical IHCs, while their presynaptic function seems to be unchanged. We conclude that piccolino contributes to the AZ organization in IHCs and is essential for normal hearing.

SUBMITTER: Ms. Susann Michanski

PROVIDER: S-SCDT-10_15252-EMBR_202256702 | biostudies-other |

REPOSITORIES: biostudies-other

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Piccolino is required for ribbon architecture at cochlear inner hair cell synapses and for hearing.

Project description:Cochlear inner hair cells (IHCs) form specialized ribbon synapses with spiral ganglion neurons that tirelessly transmit sound information at high rates over long time periods with extreme temporal precision. This functional specialization is essential for sound encoding and is attributed to a distinct molecular machinery with unique players or splice variants compared to conventional neuronal synapses. Among these is the active zone (AZ) scaffold protein piccolo/aczonin, which is represented by its short splice variant piccolino at cochlear and retinal ribbon synapses. While the function of piccolo at synapses of the central nervous system has been intensively investigated, the role of piccolino at IHC synapses remains unclear. In this study, we characterize the structure and function of IHC synapses in piccolo gene-trap mutant rats (Pclogt/gt ). We find a mild hearing deficit with elevated thresholds and reduced amplitudes of auditory brainstem responses. Ca2+ channel distribution and ribbon morphology are altered in apical IHCs, while their presynaptic function seems to be unchanged. We conclude that piccolino contributes to the AZ organization in IHCs and is essential for normal hearing.

| S-EPMC10481675 | biostudies-literature

Striatin Is Required for Hearing and Affects Inner Hair Cells and Ribbon Synapses.

Project description:Striatin, a subunit of the serine/threonine phosphatase PP2A, is a core member of the conserved striatin-interacting phosphatase and kinase (STRIPAK) complexes. The protein is expressed in the cell junctions between epithelial cells, which play a role in maintaining cell-cell adhesion. Since the cell junctions are crucial for the function of the mammalian inner ear, we examined the localization and function of striatin in the mouse cochlea. Our results show that in neonatal mice, striatin is specifically expressed in the cell-cell junctions of the inner hair cells, the receptor cells in the mammalian cochlea. Auditory brainstem response measurements of striatin-deficient mice indicated a progressive, high-frequency hearing loss, suggesting that striatin is essential for normal hearing. Moreover, scanning electron micrographs of the organ of Corti revealed a moderate degeneration of the outer hair cells in the middle and basal regions, concordant with the high-frequency hearing loss. Additionally, striatin-deficient mice show aberrant ribbon synapse maturation. Loss of the outer hair cells, combined with the aberrant ribbon synapse distribution, may lead to the observed auditory impairment. Together, these results suggest a novel function for striatin in the mammalian auditory system.

| S-EPMC7381154 | biostudies-literature

Synaptic activity is not required for establishing heterogeneity of inner hair cell ribbon synapses.

Project description:Neural sound encoding in the mammalian cochlea faces the challenge of representing audible sound pressures that vary over six orders of magnitude. The cochlea meets this demand through the use of active micromechanics as well as the diversity and adaptation of afferent neurons and their synapses. Mechanisms underlying neural diversity likely include heterogeneous presynaptic input from inner hair cells (IHCs) to spiral ganglion neurons (SGNs) as well as differences in the molecular profile of SGNs and in their efferent control. Here, we tested whether glutamate release from IHCs, previously found to be critical for maintaining different molecular SGN profiles, is required for establishing heterogeneity of active zones (AZs) in IHCs. We analyzed structural and functional heterogeneity of IHC AZs in mouse mutants with disrupted glutamate release from IHCs due to lack of a vesicular glutamate transporter (Vglut3) or impaired exocytosis due to defective otoferlin. We found the variance of the voltage-dependence of presynaptic Ca2+ influx to be reduced in exocytosis-deficient IHCs of otoferlin mutants. Yet, the spatial gradients of maximal amplitude and voltage-dependence of Ca2+ influx along the pillar-modiolar IHC axis were maintained in both mutants. Further immunohistochemical analysis showed an intact spatial gradient of ribbon size in Vglut3-/- mice. These results indicate that IHC exocytosis and glutamate release are not strictly required for establishing the heterogeneity of IHC AZs.

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Vesicle sub-pool organization at inner hair cell ribbon synapses.

Project description:The afferent inner hair cell synapse harbors the synaptic ribbon, which ensures a constant vesicle supply. Synaptic vesicles (SVs) are arranged in morphologically discernable pools, linked via filaments to the ribbon or the presynaptic membrane. We propose that filaments play a major role in SV resupply and exocytosis at the ribbon. Using advanced electron microscopy, we demonstrate that SVs are organized in sub-pools defined by the filament number per vesicle and its connections. Upon stimulation, SVs increasingly linked to other vesicles and to the ribbon, whereas single-tethered SVs dominated at the membrane. Mutant mice for the hair cell protein otoferlin (pachanga, Otof Pga/Pga ) are profoundly deaf with reduced sustained release, serving as a model to investigate the SV replenishment at IHCs. Upon stimulation, multiple-tethered and docked vesicles (rarely observed in wild-type) accumulated at Otof Pga/Pga active zones due to an impairment downstream of docking. Conclusively, vesicles are organized in sub-pools at ribbon-type active zones by filaments to support vesicle supply, transport, and finally release.

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Hidden hearing loss is associated with loss of ribbon synapses of cochlea inner hair cells.

Project description:The present study aimed to observe the changes in the cochlea ribbon synapses after repeated exposure to moderate-to-high intensity noise. Guinea pigs received 95 dB SPL white noise exposure 4 h a day for consecutive 7 days (we regarded it a medium-term and moderate-intensity noise, or MTMI noise). Animals were divided into four groups: Control, 1DPN (1-day post noise), 1WPN (1-week post noise), and 1MPN (1-month post noise). Auditory function analysis by auditory brainstem response (ABR) and compound action potential (CAP) recordings, as well as ribbon synapse morphological analyses by immunohistochemistry (Ctbp2 and PSD95 staining) were performed 1 day, 1 week, and 1 month after noise exposure. After MTMI noise exposure, the amplitudes of ABR I and III waves were suppressed. The CAP threshold was elevated, and CAP amplitude was reduced in the 1DPN group. No apparent changes in hair cell shape, arrangement, or number were observed, but the number of ribbon synapse was reduced. The 1WPN and 1MPN groups showed that part of ABR and CAP changes recovered, as well as the synapse number. The defects in cochlea auditory function and synapse changes were observed mainly in the high-frequency region. Together, repeated exposure in MTMI noise can cause hidden hearing loss (HHL), which is partially reversible after leaving the noise environment; and MTMI noise-induced HHL is associated with inner hair cell ribbon synapses.

| S-EPMC8035623 | biostudies-literature

Sensory transduction is required for normal development and maturation of cochlear inner hair cell synapses.

Project description:Acoustic overexposure and aging can damage auditory synapses in the inner ear by a process known as synaptopathy. These insults may also damage hair bundles and the sensory transduction apparatus in auditory hair cells. However, a connection between sensory transduction and synaptopathy has not been established. To evaluate potential contributions of sensory transduction to synapse formation and development, we assessed inner hair cell synapses in several genetic models of dysfunctional sensory transduction, including mice lacking transmembrane channel-like (Tmc) 1, Tmc2, or both, in Beethoven mice which carry a dominant Tmc1 mutation and in Spinner mice which carry a recessive mutation in transmembrane inner ear (Tmie). Our analyses reveal loss of synapses in the absence of sensory transduction and preservation of synapses in Tmc1-null mice following restoration of sensory transduction via Tmc1 gene therapy. These results provide insight into the requirement of sensory transduction for hair cell synapse development and maturation.

| S-EPMC8598158 | biostudies-literature

Mapping developmental maturation of inner hair cell ribbon synapses in the apical mouse cochlea.

Project description:Ribbon synapses of cochlear inner hair cells (IHCs) undergo molecular assembly and extensive functional and structural maturation before hearing onset. Here, we characterized the nanostructure of IHC synapses from late prenatal mouse embryo stages (embryonic days 14-18) into adulthood [postnatal day (P)48] using electron microscopy and tomography as well as optical nanoscopy of apical turn organs of Corti. We find that synaptic ribbon precursors arrive at presynaptic active zones (AZs) after afferent contacts have been established. These ribbon precursors contain the proteins RIBEYE and piccolino, tether synaptic vesicles and their delivery likely involves active, microtubule-based transport pathways. Synaptic contacts undergo a maturational transformation from multiple small to one single, large AZ. This maturation is characterized by the fusion of ribbon precursors with membrane-anchored ribbons that also appear to fuse with each other. Such fusion events are most frequently encountered around P12 and hence, coincide with hearing onset in mice. Thus, these events likely underlie the morphological and functional maturation of the AZ. Moreover, the postsynaptic densities appear to undergo a similar refinement alongside presynaptic maturation. Blockwise addition of ribbon material by fusion as found during AZ maturation might represent a general mechanism for modulating ribbon size.

| S-EPMC6442603 | biostudies-literature

Opposing gradients of ribbon size and AMPA receptor expression underlie sensitivity differences among cochlear-nerve/hair-cell synapses.

Project description:The auditory system transduces sound-evoked vibrations over a range of input sound pressure levels spanning six orders of magnitude. An important component of the system mediating this impressive dynamic range is established in the cochlear sensory epithelium, where functional subtypes of cochlear nerve fibers differ in threshold sensitivity, and spontaneous discharge rate (SR), by more than a factor of 1000 (Liberman, 1978), even though, regardless of type, each fiber contacts only a single hair cell via a single ribbon synapse. To study the mechanisms underlying this remarkable heterogeneity in threshold sensitivity among the 5-30 primary sensory fibers innervating a single inner hair cell, we quantified the sizes of presynaptic ribbons and postsynaptic AMPA receptor patches in >1200 synapses, using high-power confocal imaging of mouse cochleas immunostained for CtBP2 (C-terminal binding protein 2, a major ribbon protein) and GluR2/3 (glutamate receptors 2 and 3). We document complementary gradients, most striking in mid-cochlear regions, whereby synapses from the modiolar face and/or basal pole of the inner hair cell have larger ribbons and smaller receptor patches than synapses located in opposite regions of the cell. The AMPA receptor expression gradient likely contributes to the differences in cochlear nerve threshold and SR seen on the two sides of the hair cell in vivo (Liberman, 1982a); the differences in ribbon size may contribute to the heterogeneity of EPSC waveforms seen in vitro (Grant et al., 2010).

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The SNARE protein SNAP-25 is required for normal exocytosis at auditory hair cell ribbon synapses.

Project description:Hearing depends on fast and sustained calcium-dependent synaptic vesicle fusion at the ribbon synapses of cochlear inner hair cells (IHCs). The implication of the canonical neuronal SNARE complex in this exocytotic process has so far remained controversial. We investigated the role of SNAP-25, a key component of this complex, in hearing, by generating and analyzing a conditional knockout mouse model allowing a targeted postnatal deletion of Snap-25 in IHCs. Mice subjected to IHC Snap-25 inactivation after hearing onset developed severe to profound deafness because of defective IHC exocytosis followed by ribbon degeneration and IHC loss. Viral transfer of Snap-25 in these mutant mice rescued their hearing function by restoring IHC exocytosis and preventing synapses and hair cells from degeneration. These results demonstrate that SNAP-25 is essential for normal hearing function, most likely by ensuring IHC exocytosis and ribbon synapse maintenance.

| S-EPMC9722480 | biostudies-literature

N-Methyl-D-Aspartate Receptors Involvement in the Gentamicin-Induced Hearing Loss and Pathological Changes of Ribbon Synapse in the Mouse Cochlear Inner Hair Cells.

Project description:Cochlear inner hair cell (IHC) ribbon synapses play an important role in sound encoding and neurotransmitter release. Previous reports show that both noise and aminoglycoside exposures lead to reduced numbers and morphologic changes of synaptic ribbons. In this work, we determined the distribution of N-methyl-D-aspartate receptors (NMDARs) and their role in the gentamicin-induced pathological changes of cochlear IHC ribbon synaptic elements. In normal mature mouse cochleae, the majority of NMDARs were distributed on the modiolar side of IHCs and close to the IHC nuclei region, while most of synaptic ribbons and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) were located on neural terminals closer to the IHC basal poles. After gentamicin exposure, the NMDARs increased and moved towards the IHC basal poles. At the same time, synaptic ribbons and AMPARs moved toward the IHC bundle poles on the afferent dendrites. The number of ribbon synapse decreased, and this was accompanied by increased auditory brainstem response thresholds and reduced wave I amplitudes. NMDAR antagonist MK801 treatment reduced the gentamicin-induced hearing loss and the pathological changes of IHC ribbon synapse, suggesting that NMDARs were involved in gentamicin-induced ototoxicity by regulating the number and distribution of IHC ribbon synapses.

| S-EPMC6079453 | biostudies-literature

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