Alexander C. Meyer

Tuning of synapse number, structure and function in the cochlea

Cochlear inner hair cells (IHCs) transmit acoustic information to spiral ganglion neurons through ribbon synapses. Here we have used morphological and physiological techniques to ask whether synaptic mechanisms differ along the tonotopic axis and within IHCs in the mouse cochlea. We show that the number of ribbon synapses per IHC peaks where the cochlea is most sensitive to sound. Exocytosis, measured as membrane capacitance changes, scaled with synapse number when comparing apical and midcochlear IHCs. Synapses were distributed in the subnuclear portion of IHCs. High-resolution imaging of IHC synapses provided insights into presynaptic Ca2+ channel clusters and Ca2+ signals, synaptic ribbons and postsynaptic glutamate receptor clusters and revealed subtle differences in their average properties along the tonotopic axis. However, we observed substantial variability for presynaptic Ca2+ signals, even within individual IHCs, providing a candidate presynaptic mechanism for the divergent dynamics of spiral ganglion neuron spiking.

Ca2+-binding proteins tune Ca2+-feedback to Cav1.3 channels in mouse auditory hair cells

Sound coding at the auditory inner hair cell synapse requires graded changes in neurotransmitter release, triggered by sustained activation of presynaptic Cav1.3 voltage‐gated Ca2+ channels. Central to their role in this regard, Cav1.3 channels in inner hair cells show little Ca2+‐dependent inactivation, a fast negative feedback regulation by incoming Ca2+ ions, which depends on calmodulin association with the Ca2+ channel α1 subunit. Ca2+‐dependent inactivation characterizes nearly all voltage‐gated Ca2+ channels including Cav1.3 in other excitable cells. The mechanism underlying the limited autoregulation of Cav1.3 in inner hair cells remains a mystery. Previously, we established calmodulin‐like Ca2+‐binding proteins in the brain and retina (CaBPs) as essential modulators of voltage‐gated Ca2+ channels. Here, we demonstrate that CaBPs differentially modify Ca2+ feedback to Cav1.3 channels in transfected cells and explore their significance for Cav1.3 regulation in inner hair cells. Of multiple CaBPs detected in inner hair cells (CaBP1, CaBP2, CaBP4 and CaBP5), CaBP1 most efficiently blunts Ca2+‐dependent inactivation of Cav1.3. CaBP1 and CaBP4 both interact with calmodulin‐binding sequences in Cav1.3, but CaBP4 more weakly inhibits Ca2+‐dependent inactivation than CaBP1. Ca2+‐dependent inactivation is marginally greater in inner hair cells from CaBP4−/− than from wild‐type mice, yet CaBP4−/− mice are not hearing‐impaired. In contrast to CaBP4, CaBP1 is strongly localized at the presynaptic ribbon synapse of adult inner hair cells both in wild‐type and CaBP4−/− mice and therefore is positioned to modulate native Cav1.3 channels. Our results reveal unexpected diversity in the strengths of CaBPs as Ca2+ channel modulators, and implicate CaBP1 rather than CaBP4 in conferring the anomalous slow inactivation of Cav1.3 Ca2+ currents required for auditory transmission.

Structure and function of cochlear afferent innervation.

Purpose of reviewFor the perception of sound, acoustic signals need to be encoded into a neuronal code. This takes place at the inner hair cells of the organ of Corti and the afferent fibres of the auditory nerve. We will review the current knowledge of the anatomy and function of these elements as well as their connection – formed by the afferent inner hair cell synapse. Recent findingsDepending on their tonotopic location, inner hair cells are innervated by 5–30 dendrites of spiral ganglion neurons. Electrophysiological recordings from single fibres demonstrate – apart from a high-frequency selectivity – a pronounced heterogeneity in their response to sound of varying intensity. The source as well as the function of this heterogeneity is not well understood, but recent publications have suggested several mechanisms, including variations in the presynaptic Ca2+ influx and subsequent transmitter release, the postsynaptic sensitivity to neurotransmitter and electrical as well as anatomical variability of single fibres. These mechanisms might act together to expand the dynamic range of sound that can be encoded. SummaryClassical studies as well as recent publications demonstrate that sound encoding at the inner hair cell afferent synapse involves mechanisms leading to tonotopic frequency separation and distribution of intensity coding over many neuronal channels.

[Diagnosis and therapy of auditory synaptopathy/neuropathy].

ZusammenfassungDie audiologische Konstellation von pathologischen frühen akustisch evozierten Potenzialen (fehlend, erhöhte Schwelle und gestörte Kurvenform) trotz nachweisbarer otoakustischer Emissionen geht häufig mit einer von schlechtem Sprachverständnis geprägten Schwerhörigkeit bzw. mit Taubheit einher. Diese als auditorische Neuropathie erstbeschriebene, heterogene Erkrankungsgruppe beinhaltet peripher-auditorische Störungen der synaptischen Schallkodierung durch innere Haarzellen (Synaptopathie) und/oder der Erregungsbildung und -weiterleitung im Hörnerv (Neuropathie). Dieses Konsensuspapier gibt aktuelle Hintergrundinformationen sowie Empfehlungen zur Diagnostik und Therapie im deutschsprachigen Raum. Es nimmt dabei Bezug auf aktuelle internationale Statements.AbstractPathological auditory brainstem responses (lack of responses, elevated thresholds and perturbed waveforms) in combination with present otoacoustic emissions are typical audiometric findings in patients with a hearing impairment that particularly affects speech comprehension or complete deafness. This heterogenous group of disorders first described as “auditory neuropathy” includes dysfunction of peripheral synaptic coding of sound by inner hair cells (synaptopathy) and/or of the generation and propagation of action potentials in the auditory nerve (neuropathy). This joint statement provides prevailing background information as well as recommendations on diagnosis and treatment. The statement focuses on the handling in the german language area but also refers to current international statements.

[Update on physiology and pathophysiology of the inner ear: pathomechanisms of sensorineural hearing loss].

ZusammenfassungDie Schwerhörigkeit ist die häufigste humane Sinnesbehinderung. Der sensorineuralen Schwerhörigkeit (SNSH), auf die etwa 70% der Schwerhörigkeiten entfallen, liegen verschiedene pathologische Veränderungen im Innenohr und im Hörnerv zugrunde. Die individuelle Beeinträchtigung durch die SNSH und der Erfolg einer apparativen Rehabilitation hängen kritisch von den zugrunde liegenden Pathomechanismen ab. In dieser Übersicht stellen wir aktuelle Erkenntnisse über die zelluläre Pathophysiologie der SNSH vor, die überwiegend aus Studien an Mauslinien mit gezielten genetischen Modifikationen gewonnen wurden. Zuerst werden interessante Einsichten aus Experimenten von Mausmutanten mit spezifischen Defekten der kochleären Ionenhomöostase oder Verstärkung dargestellt. Wir wenden uns dann ausführlich krankhaften Veränderungen der afferenten Synapse der inneren Haarzellen (auditorische Synaptopathie) und des Hörnerven (auditorische Neuropathie) zu. Beide nosologischen Entitäten haben in den letzten Jahren auch große klinische Beachtung gefunden. Diesen SNSH-Varianten ist die gestörte zeitliche Verarbeitung von Schallsignalen gemeinsam. Daraus resultiert ein besonders schlechtes Sprachverständnis, dessen Störung oft über das von der Tonschwelle erwartete Maß hinausgeht. Das Ausmaß der Schwerhörigkeit reicht von milden Formen mit Defizit ausschließlich in der zeitlichen Verarbeitung von Schallsignalen bis hin zur Taubheit. Dabei sind otoakustische Emissionen als Zeichen einer normalen kochleären Verstärkung zumindest initial häufig zu beobachten.Zusammenfassend kann gesagt werden, dass gut charakterisierte Tiermodelle unser pathophysiologisches Verständnis der SNSH vertiefen. Sie leisten wertvolle Hilfe bei der Etablierung neuer audiologischer Protokolle zur Differenzierung der einer individuellen SNSH zugrunde liegenden Pathomechanismen. Auf diese Weise tragen sie zur gezielten Diagnostik und Rehabilitation von SNSH-Patienten bei.AbstractHearing impairment is the most common form of human sensory deficit. The most frequent form, sensorineural hearing loss (SNHL), which accounts for approximately 70% of cases, encompasses various pathologies in both the inner ear and the auditory nerve. The individual hearing impairment and its outcome following aiding with hearing devices critically depend on the underlying disorder. Here recent progress in our understanding of the cellular mechanisms of SNHL in genetically engineered mouse models is reviewed. First, insights gained from models for specific defects in cochlear sound amplification and ion homeostasis are discussed followed by a focus on disorders of the inner hair cell synapses (auditory synaptopathy) and the auditory nerve (auditory neuropathy). Both nosological entities have also attracted substantial clinical interest in recent years and share an impaired temporal processing of auditory stimuli. This results in poor speech recognition, often out of proportion to the pure tone threshold. Hearing loss can range from mild variants with exclusive deficits of temporal processing to complete deafness. At least initially, signs of normal outer hair cell function such as evoked otoacoustic emissions can be found. In summary, well-characterized animal models allow us to refine our pathophysiological understanding of SNHL and offer invaluable help in defining toolboxes for investigating the mechanism(s) underlying the SNHL of affected individuals. Together, this will contribute to custom-tailored diagnostics and rehabilitation of SNHL patients.Hearing impairment is the most common form of human sensory deficit. The most frequent form, sensorineural hearing loss (SNHL), which accounts for approximately 70% of cases, encompasses various pathologies in both the inner ear and the auditory nerve. The individual hearing impairment and its outcome following aiding with hearing devices critically depend on the underlying disorder. Here recent progress in our understanding of the cellular mechanisms of SNHL in genetically engineered mouse models is reviewed. First, insights gained from models for specific defects in cochlear sound amplification and ion homeostasis are discussed followed by a focus on disorders of the inner hair cell synapses (auditory synaptopathy) and the auditory nerve (auditory neuropathy). Both nosological entities have also attracted substantial clinical interest in recent years and share an impaired temporal processing of auditory stimuli. This results in poor speech recognition, often out of proportion to the pure tone threshold. Hearing loss can range from mild variants with exclusive deficits of temporal processing to complete deafness. At least initially, signs of normal outer hair cell function such as evoked otoacoustic emissions can be found. In summary, well-characterized animal models allow us to refine our pathophysiological understanding of SNHL and offer invaluable help in defining toolboxes for investigating the mechanism(s) underlying the SNHL of affected individuals. Together, this will contribute to custom-tailored diagnostics and rehabilitation of SNHL patients.

Mastoid Cavity Obliteration and Vibrant Soundbridge Implantation for Patients With Mixed Hearing Loss

To review the results of obliteration of a preexisting mastoid cavity with abdominal fat and Vibrant Soundbridge implantation in patients with mixed hearing loss (MHL) and to compare the data with results of Vibrant Soundbridge implantation in patients with MHL without mastoid cavity and with pure sensorineural hearing loss (SNHL).

Propagation-based phase-contrast x-ray tomography of cochlea using a compact synchrotron source

We demonstrate that phase retrieval and tomographic imaging at the organ level of small animals can be advantageously carried out using the monochromatic radiation emitted by a compact x-ray light source, without further optical elements apart from source and detector. This approach allows to carry out microtomography experiments which - due to the large performance gap with respect to conventional laboratory instruments - so far were usually limited to synchrotron sources. We demonstrate the potential by mapping the functional soft tissue within the guinea pig and marmoset cochlea, including in the latter case an electrical cochlear implant. We show how 3d microanatomical studies without dissection or microscopic imaging can enhance future research on cochlear implants.

Update zur Physiologie und Pathophysiologie des Innenohrs@@@Update on physiology and pathophysiology of the inner ear: Pathomechanismen der sensorineuralen Schwerhörigkeit@@@Pathomechanisms of sensorineural hearing loss

ZusammenfassungDie Schwerhörigkeit ist die häufigste humane Sinnesbehinderung. Der sensorineuralen Schwerhörigkeit (SNSH), auf die etwa 70% der Schwerhörigkeiten entfallen, liegen verschiedene pathologische Veränderungen im Innenohr und im Hörnerv zugrunde. Die individuelle Beeinträchtigung durch die SNSH und der Erfolg einer apparativen Rehabilitation hängen kritisch von den zugrunde liegenden Pathomechanismen ab. In dieser Übersicht stellen wir aktuelle Erkenntnisse über die zelluläre Pathophysiologie der SNSH vor, die überwiegend aus Studien an Mauslinien mit gezielten genetischen Modifikationen gewonnen wurden. Zuerst werden interessante Einsichten aus Experimenten von Mausmutanten mit spezifischen Defekten der kochleären Ionenhomöostase oder Verstärkung dargestellt. Wir wenden uns dann ausführlich krankhaften Veränderungen der afferenten Synapse der inneren Haarzellen (auditorische Synaptopathie) und des Hörnerven (auditorische Neuropathie) zu. Beide nosologischen Entitäten haben in den letzten Jahren auch große klinische Beachtung gefunden. Diesen SNSH-Varianten ist die gestörte zeitliche Verarbeitung von Schallsignalen gemeinsam. Daraus resultiert ein besonders schlechtes Sprachverständnis, dessen Störung oft über das von der Tonschwelle erwartete Maß hinausgeht. Das Ausmaß der Schwerhörigkeit reicht von milden Formen mit Defizit ausschließlich in der zeitlichen Verarbeitung von Schallsignalen bis hin zur Taubheit. Dabei sind otoakustische Emissionen als Zeichen einer normalen kochleären Verstärkung zumindest initial häufig zu beobachten.Zusammenfassend kann gesagt werden, dass gut charakterisierte Tiermodelle unser pathophysiologisches Verständnis der SNSH vertiefen. Sie leisten wertvolle Hilfe bei der Etablierung neuer audiologischer Protokolle zur Differenzierung der einer individuellen SNSH zugrunde liegenden Pathomechanismen. Auf diese Weise tragen sie zur gezielten Diagnostik und Rehabilitation von SNSH-Patienten bei.AbstractHearing impairment is the most common form of human sensory deficit. The most frequent form, sensorineural hearing loss (SNHL), which accounts for approximately 70% of cases, encompasses various pathologies in both the inner ear and the auditory nerve. The individual hearing impairment and its outcome following aiding with hearing devices critically depend on the underlying disorder. Here recent progress in our understanding of the cellular mechanisms of SNHL in genetically engineered mouse models is reviewed. First, insights gained from models for specific defects in cochlear sound amplification and ion homeostasis are discussed followed by a focus on disorders of the inner hair cell synapses (auditory synaptopathy) and the auditory nerve (auditory neuropathy). Both nosological entities have also attracted substantial clinical interest in recent years and share an impaired temporal processing of auditory stimuli. This results in poor speech recognition, often out of proportion to the pure tone threshold. Hearing loss can range from mild variants with exclusive deficits of temporal processing to complete deafness. At least initially, signs of normal outer hair cell function such as evoked otoacoustic emissions can be found. In summary, well-characterized animal models allow us to refine our pathophysiological understanding of SNHL and offer invaluable help in defining toolboxes for investigating the mechanism(s) underlying the SNHL of affected individuals. Together, this will contribute to custom-tailored diagnostics and rehabilitation of SNHL patients.Hearing impairment is the most common form of human sensory deficit. The most frequent form, sensorineural hearing loss (SNHL), which accounts for approximately 70% of cases, encompasses various pathologies in both the inner ear and the auditory nerve. The individual hearing impairment and its outcome following aiding with hearing devices critically depend on the underlying disorder. Here recent progress in our understanding of the cellular mechanisms of SNHL in genetically engineered mouse models is reviewed. First, insights gained from models for specific defects in cochlear sound amplification and ion homeostasis are discussed followed by a focus on disorders of the inner hair cell synapses (auditory synaptopathy) and the auditory nerve (auditory neuropathy). Both nosological entities have also attracted substantial clinical interest in recent years and share an impaired temporal processing of auditory stimuli. This results in poor speech recognition, often out of proportion to the pure tone threshold. Hearing loss can range from mild variants with exclusive deficits of temporal processing to complete deafness. At least initially, signs of normal outer hair cell function such as evoked otoacoustic emissions can be found. In summary, well-characterized animal models allow us to refine our pathophysiological understanding of SNHL and offer invaluable help in defining toolboxes for investigating the mechanism(s) underlying the SNHL of affected individuals. Together, this will contribute to custom-tailored diagnostics and rehabilitation of SNHL patients.