RIM-Binding Proteins Are Required for Normal Sound-Encoding at Afferent Inner Hair Cell Synapses

The afferent synapses between inner hair cells (IHC) and spiral ganglion neurons are specialized to faithfully encode sound with sub-millisecond precision over prolonged periods of time. Here, we studied the role of Rab3 interacting molecule-binding proteins (RIM-BP) 1 and 2 – multidomain proteins of the active zone known to directly interact with RIMs, Bassoon and CaV1.3 – in IHC presynaptic function and hearing. Recordings of auditory brainstem responses and otoacoustic emissions revealed that genetic disruption of RIM-BPs 1 and 2 in mice (RIM-BP1/2–/–) causes a synaptopathic hearing impairment exceeding that found in mice lacking RIM-BP2 (RIM-BP2–/–). Patch-clamp recordings from RIM-BP1/2–/– IHCs indicated a subtle impairment of exocytosis from the readily releasable pool of synaptic vesicles that had not been observed in RIM-BP2–/– IHCs. In contrast, the reduction of Ca2+-influx and sustained exocytosis was similar to that in RIMBP2–/– IHCs. We conclude that both RIM-BPs are required for normal sound encoding at the IHC synapse, whereby RIM-BP2 seems to take the leading role.

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Consecutive Treatment with Brain-Derived Neurotrophic Factor and Electrical Stimulation Has a Protective Effect on Primary Auditory Neurons

Brain Sciences ◽

10.3390/brainsci10080559 ◽

2020 ◽

Vol 10 (8) ◽

pp. 559 ◽

Cited By ~ 2

Author(s):

Verena Scheper ◽

Ira Seidel-Effenberg ◽

Thomas Lenarz ◽

Timo Stöver ◽

Gerrit Paasche

Keyword(s):

Electrical Stimulation ◽

Neurotrophic Factor ◽

Combined Treatment ◽

Spiral Ganglion ◽

Brain Derived Neurotrophic Factor ◽

Auditory Brainstem ◽

Contralateral Side ◽

Auditory Brainstem Responses ◽

Drug Delivery Device ◽

Ganglion Neurons

Degeneration of neurons, such as the inner ear spiral ganglion neurons (SGN), may be decelerated or even stopped by neurotrophic factor treatment, such as brain-derived neurotrophic factor (BDNF), as well as electrical stimulation (ES). In a clinical setting, drug treatment of the SGN could start directly during implantation of a cochlear implant, whereas electrical stimulation begins days to weeks later. The present study was conducted to determine the effects of consecutive BDNF and ES treatments on SGN density and electrical responsiveness. An electrode drug delivery device was implanted in guinea pigs 3 weeks after deafening and five experimental groups were established: two groups received intracochlear infusion of artificial perilymph (AP) or BDNF; two groups were treated with AP respectively BDNF in addition to ES (AP + ES, BDNF + ES); and one group received BDNF from the day of implantation until day 34 followed by ES (BDNF ⇨ ES). Electrically evoked auditory brainstem responses were recorded. After one month of treatment, the tissue was harvested and the SGN density was assessed. The results show that consecutive treatment with BDNF and ES was as successful as the simultaneous combined treatment in terms of enhanced SGN density compared to the untreated contralateral side but not in regard to the numbers of protected cells.

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Rab3-interacting molecules 2α and 2β promote the abundance of voltage-gated CaV1.3 Ca2+ channels at hair cell active zones

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1417207112 ◽

2015 ◽

Vol 112 (24) ◽

pp. E3141-E3149 ◽

Cited By ~ 30

Author(s):

Sangyong Jung ◽

Tomoko Oshima-Takago ◽

Rituparna Chakrabarti ◽

Aaron B. Wong ◽

Zhizi Jing ◽

...

Keyword(s):

Hair Cell ◽

Electron Tomography ◽

Spiral Ganglion ◽

Auditory Brainstem ◽

Auditory Brainstem Responses ◽

Fluctuation Analysis ◽

Superresolution Microscopy ◽

Voltage Gated ◽

Ganglion Neurons ◽

Specific Deletion

Ca2+ influx triggers the fusion of synaptic vesicles at the presynaptic active zone (AZ). Here we demonstrate a role of Ras-related in brain 3 (Rab3)–interacting molecules 2α and β (RIM2α and RIM2β) in clustering voltage-gated CaV1.3 Ca2+ channels at the AZs of sensory inner hair cells (IHCs). We show that IHCs of hearing mice express mainly RIM2α, but also RIM2β and RIM3γ, which all localize to the AZs, as shown by immunofluorescence microscopy. Immunohistochemistry, patch-clamp, fluctuation analysis, and confocal Ca2+ imaging demonstrate that AZs of RIM2α-deficient IHCs cluster fewer synaptic CaV1.3 Ca2+ channels, resulting in reduced synaptic Ca2+ influx. Using superresolution microscopy, we found that Ca2+ channels remained clustered in stripes underneath anchored ribbons. Electron tomography of high-pressure frozen synapses revealed a reduced fraction of membrane-tethered vesicles, whereas the total number of membrane-proximal vesicles was unaltered. Membrane capacitance measurements revealed a reduction of exocytosis largely in proportion with the Ca2+ current, whereas the apparent Ca2+ dependence of exocytosis was unchanged. Hair cell-specific deletion of all RIM2 isoforms caused a stronger reduction of Ca2+ influx and exocytosis and significantly impaired the encoding of sound onset in the postsynaptic spiral ganglion neurons. Auditory brainstem responses indicated a mild hearing impairment on hair cell-specific deletion of all RIM2 isoforms or global inactivation of RIM2α. We conclude that RIM2α and RIM2β promote a large complement of synaptic Ca2+ channels at IHC AZs and are required for normal hearing.

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R449 – The Role of DPZF in Inner Ear Development and Function

Otolaryngology ◽

10.1016/j.otohns.2008.05.605 ◽

2008 ◽

Vol 139 (2_suppl) ◽

pp. P195-P195

Author(s):

Gao Xia

Keyword(s):

Electron Microscopy ◽

Scanning Electron Microscopy ◽

Inner Ear ◽

Hair Cells ◽

Otoacoustic Emissions ◽

Auditory Brainstem ◽

Auditory Brainstem Responses ◽

Inner Ear Development ◽

Scanning Electron

Problem The dendritic cell-derived BTB/POZ zinc finger (DPZF) protein belongs to the C2H2 zinc finger protein transcription factor family. It is localized on chromosome 3 and widely expressed in hematopoietic tissues, including human dendritic cells (DC), monocytes, B cells and T cells. DPZF null mice (DPZF-/-) exhibit a circling phenotype, suggestive of an inner ear defect. Here, we present our work on the role of DPZF in hearing defects. Methods We used auditory brainstem responses (ABR) and distortion production otoacoustic emissions (DPOAEs) to test the hearing function of DPZF-/- mice, then gross observation and histopathology analysis including serial sections and scanning electron microscopy were performed to exam the cochlea of DPZF-/- mice. Results Auditory brainstem responses (ABR) and distortion production otoacoustic emissions (DPOAEs) showed that DPZF-/-mice were completely deaf. Disorganized and fewer hair cells of the Corti organ in DPZF-/- mice were identified by scanning electron microscopy. Besides, although the hair cells of the utricle and saccule were grossly normal, the stereocilia were greatly reduced in number. Further more, lipofuscin was seen in the stria vascularis with the amount of which increased with age. Conclusion The impaired hearing and balance function and the morphological abnormalities of inner ears are caused by the deletion of DPZF gene. Significance DPZF gene may participates in regulating inner ear development and the DPZF null mice may serve as a new disease model of hearing loss. Support This work was supported by the ground of Jiangsu Province Famous Doctor Project(RC2007010).

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Functional contributions of HCN channels in the primary auditory neurons of the mouse inner ear

The Journal of General Physiology ◽

10.1085/jgp.201311019 ◽

2013 ◽

Vol 142 (3) ◽

pp. 207-223 ◽

Cited By ~ 28

Author(s):

Ye-Hyun Kim ◽

Jeffrey R. Holt

Keyword(s):

Signal Transmission ◽

Spiral Ganglion ◽

Auditory Brainstem ◽

Spike Timing ◽

Membrane Properties ◽

Auditory Brainstem Responses ◽

Resting Potential ◽

Hcn Channels ◽

Adult Mice ◽

Ganglion Neurons

The hyperpolarization-activated current, Ih, is carried by members of the Hcn channel family and contributes to resting potential and firing properties in excitable cells of various systems, including the auditory system. Ih has been identified in spiral ganglion neurons (SGNs); however, its molecular correlates and their functional contributions have not been well characterized. To investigate the molecular composition of the channels that carry Ih in SGNs, we examined Hcn mRNA harvested from spiral ganglia of neonatal and adult mice using quantitative RT-PCR. The data indicate expression of Hcn1, Hcn2, and Hcn4 subunits in SGNs, with Hcn1 being the most highly expressed at both stages. To investigate the functional contributions of HCN subunits, we used the whole-cell, tight-seal technique to record from wild-type SGNs and those deficient in Hcn1, Hcn2, or both. We found that HCN1 is the most prominent subunit contributing to Ih in SGNs. Deletion of Hcn1 resulted in reduced conductance (Gh), slower activation kinetics (τfast), and hyperpolarized half-activation (V1/2) potentials. We demonstrate that Ih contributes to SGN function with depolarized resting potentials, depolarized sag and rebound potentials, accelerated rebound spikes after hyperpolarization, and minimized jitter in spike latency for small depolarizing stimuli. Auditory brainstem responses of Hcn1-deficient mice showed longer latencies, suggesting that HCN1-mediated Ih is critical for synchronized spike timing in SGNs. Together, our data indicate that Ih contributes to SGN membrane properties and plays a role in temporal aspects of signal transmission between the cochlea and the brain, which are critical for normal auditory function.

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Contralateral Suppression of DPOAEs in Mice after Ouabain Treatment

Neural Plasticity ◽

10.1155/2018/6890613 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Jieying Li ◽

Yan Chen ◽

Shan Zeng ◽

Chuijin Lai ◽

Yanping Zhang ◽

...

Keyword(s):

Otoacoustic Emissions ◽

Round Window ◽

Spiral Ganglion ◽

Auditory Brainstem ◽

Spiral Ganglion Neurons ◽

Type I ◽

Type Ii ◽

Contralateral Suppression ◽

Brainstem Response ◽

Ganglion Neurons

Medial olivocochlear (MOC) efferent feedback is suggested to protect the ear from acoustic injury and to increase its ability to discriminate sounds against a noisy background. We investigated whether type II spiral ganglion neurons participate in the contralateral suppression of the MOC reflex. The application of ouabain to the round window of the mouse cochlea selectively induced the apoptosis of the type I spiral ganglion neurons, left the peripherin-immunopositive type II spiral ganglion neurons intact, and did not affect outer hairs, as evidenced by the maintenance of the distorted product otoacoustic emissions (DPOAEs). With the ouabain treatment, the threshold of the auditory brainstem response increased significantly and the amplitude of wave I decreased significantly in the ouabain-treated ears, consistent with the loss of type I neurons. Contralateral suppression was measured as reduction in the amplitude of the 2f1−f2 DPOAEs when noise was presented to the opposite ear. Despite the loss of all the type I spiral ganglion neurons, virtually, the amplitude of the contralateral suppression was not significantly different from the control when the suppressor noise was delivered to the treated cochlea. These results are consistent with the type II spiral ganglion neurons providing the sensory input driving contralateral suppression of the MOC reflex.

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Auditory neuropathy in a patient with mitochondrial myopathy and multiple mtDNA deletions

The Journal of Laryngology & Otology ◽

10.1017/s0022215106001472 ◽

2006 ◽

Vol 120 (10) ◽

pp. 888-891 ◽

Cited By ~ 9

Author(s):

F Forli ◽

M Mancuso ◽

A Santoro ◽

M T Dotti ◽

G Siciliano ◽

...

Keyword(s):

Hair Cells ◽

Otoacoustic Emissions ◽

Mitochondrial Myopathy ◽

Spiral Ganglion ◽

Mitochondrial Diseases ◽

Auditory Brainstem ◽

Auditory Neuropathy ◽

Auditory Brainstem Responses ◽

Common Symptom ◽

First Case

Auditory neuropathy (AN) is a hearing disorder characterized by the absence or severe distortion of the auditory brainstem responses, in the presence of preserved otoacoustic emissions. This peculiar combination suggests the presence of a defect impinging upon the functional complex formed by inner hair cells, the primary afferents (spiral ganglion neurones) and the first order synapses between hair cells and the cochlear nerve. Typically, AN patients show a severe speech perception impairment, which appears reduced out of proportion to pure tone threshold, but the clinical presentation of AN is quite complex.Hearing loss is a common symptom associated with mitochondrial diseases; however, AN has only rarely been reported in these disorders.Here we report a rare association, the first case observed in Italy, in a patient with autosomal recessive mitochondrial myopathy and mitochondrial DNA multiple deletions, and a hearing deficit with the audiological and electrophysiological features of AN.

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Effect of Electroacupuncture on Noise-Induced Hearing Loss in Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/9114676 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Chia-Hao Chang ◽

Chia-Der Lin ◽

Ching-Liang Hsieh

Keyword(s):

Hearing Loss ◽

Noise Exposure ◽

Histopathological Examination ◽

Spiral Ganglion ◽

Auditory Brainstem ◽

Auditory Threshold ◽

Auditory Brainstem Responses ◽

Control Group ◽

Noise Induced Hearing Loss ◽

Ganglion Neurons

Acupuncture has long been used to relieve some inner ear diseases such as deafness and tinnitus. The present study examined the effect of electroacupuncture (EA) on noise-induced hearing loss (NIHL) in animals. A NIHL rat model was established. Electroacupuncture pretreatment at 2 Hz or posttreatment at the right Zhongzhu (TE3) acupoint was applied for 1 hour. Auditory thresholds were measured using auditory brainstem responses (ABRs), and histopathology of the cochlea was examined. The results indicated that the baseline auditory threshold of ABR was not significantly different between the control (no noise), EA-only (only EA without noise), noise (noise exposure only), pre-EA (pretreating EA then noise), and post-EA (noise exposure then posttreating with EA) groups. Significant auditory threshold shifts were found in the noise, pre-EA, and post-EA groups in the immediate period after noise exposure, whereas auditory recovery was better in the pre-EA and post-EA groups than that in the noise group at the three days, one week (W1), two weeks (W2), three weeks (W3), and four weeks(W4) after noise stimulation. Histopathological examination revealed greater loss of the density of spiral ganglion neurons in the noise group than in the control group at W1 and W2. Although significant loss of spiral ganglion loss happened in pre-EA and post-EA groups, such loss was less than the loss of the noise group, especially W1. These results indicate that either pretreatment or posttreatment with EA may facilitate auditory recovery after NIHL. The detailed mechanism through which EA alleviates NIHL requires further study.

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Audiological findings in glomus tumours

The Journal of Laryngology & Otology ◽

10.1017/s0022215100136953 ◽

1997 ◽

Vol 111 (3) ◽

pp. 218-222 ◽

Cited By ~ 2

Author(s):

William W. Qiu ◽

Shengguang S. Yin ◽

Fred J. Stucker ◽

Mardjohan Hardjasudarma

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Auditory System ◽

Middle Ear ◽

Otoacoustic Emissions ◽

Cerebellopontine Angle ◽

Auditory Brainstem ◽

Auditory Brainstem Responses ◽

Resonance Imaging ◽

Magnetic Resonance Imaging Mri

AbstractGlomus tumours involving the middle ear and the cerebellopontine angle are reported with emphasis on audiological findings. Magnetic resonance imaging (MRI), angiographic and pathological results are presented. Audiological tests, including impedance audiometry, evoked otoacoustic emissions and auditory brainstem responses, are valuable in evaluation of the effect of glomus tumours on the auditory system as well as their pathological extent.

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Μελέτη των παραγόντων υψηλού κινδύνου για εμφάνιση βαρηκοΐας σε νεογνά της μονάδας εντατικής νοσηλείας

10.12681/eadd/39580 ◽

2016 ◽

Author(s):

Εμμανουήλ Νησωτάκης

Keyword(s):

Otoacoustic Emissions ◽

Auditory Brainstem ◽

Auditory Brainstem Responses ◽

Transiently Evoked Otoacoustic Emissions

Εισαγωγή Η συγγενής βαρηκοΐα είναι ίσως η πιο συχνή αισθητηριακή βλάβη της νεογνικής ηλικίας. Τα νοσηλευόμενα στη ΜΕΝΝ νεογνά θεωρείται ότι διατρέχουν μεγαλύτερο κίνδυνο για εμφάνιση είτε νευροαισθητήριας βαρηκοΐας είτε ακουστικής νευροπάθειας. Η σοβαρότητα της απώλειας ακοής κατά τη διάρκεια της πρώιμης κρίσιμης περιόδου ανάπτυξης του λόγου καθορίζει την απόκτηση επαρκούς γλωσσικής ικανότητας γι’ αυτό και είναι σημαντική η έγκαιρη διάγνωση και αντιμετώπιση κάθε υποκείμενης ακουστικής διαταραχής.Στη μελέτη αυτή εστιάζουμε στην παρουσία ακοολογικών παραγόντων κινδύνου και προσπαθούμε να διευκρινίσουμε την συσχέτισή τους με την εμφάνιση συγγενούς βαρηκοΐας, συμπεριλαμβανομένης και της ακουστικής νευροπάθειας, στον πληθυσμό των νεογνών της ΜΕΝΝ του νοσοκομείου μας.Ασθενείς και ΜέθοδοςΣτην παρούσα προοπτική μελέτη κοόρτης μελετήθηκαν 453 νεογνά τα οποία εισήχθησαν στη ΜΕΝΝ για περισσότερο από 24 ώρες μεταξύ 2012 και 2016 και εμφάνιζαν έναν ή περισσότερους παράγοντες κινδύνου. Όλα τα νεογνά υποβλήθηκαν σε ακοολογικό έλεγχο με χρήση αυτοματοποιημένων προκλητών δυναμικών του εγκεφαλικού στελέχους (automated Auditory Brainstem Responses – aABRs) σε συνδυασμό με παροδικά προκλητές ωτοακουστικές εκπομπές (Transiently Evoked OtoAcoustic Emissions – TEOAEs) τουλάχιστον 48 ώρες μετά τη γέννησή τους. Τα νεογνά που απέτυχαν στην αρχική εξέταση επανεξετάζονταν πριν τον πρώτο μήνα ζωής κι επί αποτυχίας παραπέμπονταν στο ιατρείο παιδικής βαρηκοΐας για πλήρη ακοολογικό έλεγχο. ΑποτελέσματαΑπό τον συνολικό αριθμό των 453 νεογνών 71 απέτυχαν στον αρχικό ακοολογικό έλεγχο. Μόνο 49 προσήλθαν για επανεξέταση και τελικά 8 νεογνά (1.8%) απέτυχαν τόσο στα a-ABRs όσο και στις TEOAEs και διαγνώσθηκαν με πιθανή νευροαισθητήρια βαρηκοΐα, ενώ σε επίσης 8 νεογνά (1.8%) οι TEOAEs εκλύθηκαν φυσιολογικά αλλά απέτυχαν στα a-ABRs οπότε διαγνώσθηκαν με πιθανή ακουστική νευροπάθεια. Από τους 13 ανεξάρτητους παράγοντες κινδύνου που ελέγχθηκαν η ωτοτοξικότητα των χορηγούμενων φαρμάκων, η μηχανική υποστήριξη της αναπνοής, το χαμηλό βάρος γέννησης και η υπερχολερυθριναιμία ήταν οι πιο συχνά εμφανιζόμενοι. Η πλειοψηφία των νεογνών (48%) εμφάνιζε ταυτόχρονα δύο παράγοντες κινδύνου. Το χαμηλό βάρος γέννησης βρέθηκε να συσχετίζεται με την εμφάνιση πιθανής νευροαισθητήριας βαρηκοΐας (p=0.002), ενώ οι κρανιοπροσωπικές ανωμαλίες και οι λοιμώξεις της ομάδας TORCH παρουσίασαν στατιστικά σημαντική συμμετοχή (p=0.03 και p=0.05 αντίστοιχα) στην ανάπτυξη πιθανής απώλειας ακοής συμπεριλαμβανομένης και της ακουστικής νευροπάθειας.ΣυμπεράσματαΤα προκλητά δυναμικά του εγκεφαλικού στελέχους (ABRs) και οι ωτοακουστικές εκπομπές (OAEs) αποτελούν τους θεμέλιους λίθους του καθολικού νεογνικού ελέγχου ακοής στη ΜΕΝΝ καθώς σημαντικός αριθμός παιδιών μπορεί να πάσχει από ακουστική νευροπάθεια. Η συνεχής επανεξέταση των παραγόντων κινδύνου και της συμβολής τους στην εμφάνιση βαρηκοΐας κρίνεται απαραίτητη καθώς αυτοί μεταβάλλονται. Απαιτείται ένα αποδοτικό σύστημα γραμματειακής υποστήριξης προκειμένου να ελαττωθεί το ποσοστό των νεογνών που δεν προσέρχονται για επανεξέταση.

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