1,720,959 research outputs found
CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells
No full textCaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells
No full textTo encode continuous sound stimuli, the inner hair cell (IHC) ribbon synapses utilize calcium-binding proteins (CaBPs), which reduce the inactivation of their Ca V 1.3 calcium channels. Mutations in the CABP2 gene underlie non-syndromic autosomal recessive hearing loss DFNB93. Besides CaBP2, the structurally related CaBP1 is highly abundant in the IHCs. Here, we investigated how the two CaBPs cooperatively regulate IHC synaptic function. In Cabp1/2 double-knockout mice, we find strongly enhanced Ca V 1.3 inactivation, slowed recovery from inactivation and impaired sustained exocytosis. Already mild IHC activation further reduces the availability of channels to trigger synaptic transmission and may effectively silence synapses. Spontaneous and sound-evoked responses of spiral ganglion neurons in vivo are strikingly reduced and strongly depend on stimulation rates. Transgenic expression of CaBP2 leads to substantial recovery of IHC synaptic function and hearing sensitivity. We conclude that CaBP1 and 2 act together to suppress voltage and calcium-dependent inactivation of IHC Ca V 1.3 channels in order to support sufficient rate of exocytosis and enable fast, temporally precise and indefatigable sound encoding
A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2
No full textAuditory synaptopathy/neuropathy (AS/AN) is a distinct type of sensorineural hearing loss in which the cochlear sensitivity to sound (i.e. active cochlear amplification by outer hair cells) is preserved whereas sound encoding by inner hair cells and/or auditory nerve fibers is disrupted due to genetic or environmental factors. Autosomal-dominant auditory neuropathy type 2 (AUNA2) was linked either to chromosomal bands 12q24 or 13q34 in a large German family in 2017. By whole genome sequencing, we now detected a 5500 bp deletion in ATP11A on chromosome 13q34 segregating with the phenotype in this family. ATP11A encodes a P-type ATPase that translocates phospholipids from the exoplasmic to the cytoplasmic leaflet of the plasma membrane. The deletion affects both isoforms of ATP11A and activates a cryptic splice site leading to the formation of an alternative last exon. ATP11A carrying the altered C-terminus loses its flippase activity for phosphatidylserine. Atp11a is expressed in fibers and synaptic contacts of the auditory nerve and in the cochlear nucleus in mice and conditional Atp11a knockout mice show a progressive reduction of the spiral ganglion neuron compound action potential, recapitulating the human phenotype of auditory neuropathy. By combining whole genome sequencing, immunohistochemistry, in vitro functional assays and generation of a mouse model, we could thus identify a partial deletion of ATP11A as the genetic cause of AUNA2
Eine Mutation in Atp11a verursacht die autosomal dominant vererbte auditorische Neuropathie Typ 2 (AUNA2).
No full textAuditory nerve function in mouse models of ATP11A and CABP1-CABP2 related hearing loss
Get PDFHearing loss can be caused by varied factors affecting diverse structures of the auditory system such as the middle ear, the stria vascularis, the outer hair cells (OHC), inner hair cells (IHC), the spiral ganglion neurons (SGN), and the central auditory system. Auditory synaptopathy/neuropathy is a hearing disorder caused by deficits of the IHC ribbon synapses or the SGNs. Clinically, it is characterized by absent or severely abnormal auditory brainstem responses (ABRs) and conserved function of the OHCs determined by preserved Distortion Product Otoacoustic Emissions (DPOAEs). Here, I use genetically modified mouse models to study the mechanisms of two independent genetic causes of auditory neuropathy, autosomal dominant auditory neuropathy type II (AUNA2) caused by mutations in ATP11A and autosomal recessive auditory synaptopathy DFNB93 caused by mutations in CABP2.
Like AUNA2 patients, conditional Atp11a knockout mice showed an age-dependent reduction in ABR amplitudes. However, the single unit responses of their SGNs were quite normal. Interestingly, we observed a reduction in peak firing rates which together with a reduction in the number of IHC-SGN synapses may explain the ABR phenotype. In contrast, the very strong ABR amplitude reduction in Cabp1-Cabp2 double knockout mice was found to correlate with a drastic reduction of SGN action potential firing. Enhanced synaptic CaV1.3 Ca2+ channel inactivation in the IHCs led to enhanced SGN firing rate adaptation. By increasing the duration of the silent interstimulus interval, I observed that the sound onset spike rates of mutants improved with an increased jitter and latency of the first-spike. These observations suggest the synergistic action of Cabp1-Cabp2 is crucial for maintaining the calcium channels in a non-inactivated state and for sustained synaptic transmission at IHC ribbon synapses.
The comparison between the two mutants underlines that very diverse processes can cause auditory neuropathy and suggest that the clinical interventions to restore hearing need to thus focus on specific functional units of the auditory system. This study implicates the electrophysiological investigations in the auditory nerve as a crucial and essential experiment to confirm and assess the severity of an auditory deficit, to functionally characterize the phenotype of auditory neurotransmission and effectively elucidate the disease mechanism of etiologically diverse hearing disorders.2025-02-1
Ca2+-binding to the C2E domain of otoferlin is required for hair cell exocytosis and hearing
No full textA mutation in Atp11a causes autosomal dominant inherited auditory neuropathy type 2 (AUNA2).
No full text
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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