Koleilat, Alaa

Our understanding of inner ear hair cell ultrastructure has heretofore relied upon two-dimensional imaging; however, serial block-face scanning electron microscopy (SBFSEM) changes this paradigm allowing for three-dimensional evaluation. We compared inner ear hair cells of the apical cristae in myo7aa −/− null zebrafish, a model of human Usher Syndrome type 1B, to hair cells in wild-type zebrafish by SBFSEM to investigate possible ribbon synapse ultrastructural differences. Previously, it has been shown that compared to wild type, myo7aa −/− zebrafish neuromast hair cells have fewer ribbon synapses yet similar ribbon areas. We expect the recapitulation of these results within the inner ear apical crista hair cells furthering the knowledge of three-dimensional ribbon synapse structure while resolving the feasibility of therapeutically targeting myo7aa −/− mutant ribbons. In this report, we evaluated ribbon synapse number, volume, surface area, and sphericity. Localization of ribbons and their distance from the nearest innervation were also evaluated. We determined that myo7aa −/− mutant ribbon synapses are smaller in volume and surface area; however, all other measurements were not significantly different from wild-type zebrafish. Because the ribbon synapses are nearly indistinguishable between the myo7aa −/− mutant and wild type, it suggests that the ribbons are structurally receptive, supporting that therapeutic intervention may be feasible.

ABSTRACT The mariner (myo7aa−/−) mutant is a zebrafish model for Usher syndrome type 1 (USH1). To further characterize hair cell synaptic elements in myo7aa−/− mutants, we focused on the ribbon synapse and evaluated ultrastructure, number and distribution of immunolabeled ribbons, and postsynaptic densities. By transmission electron microscopy, we determined that myo7aa−/− zebrafish have fewer glutamatergic vesicles tethered to ribbon synapses, yet maintain a comparable ribbon area. In myo7aa−/− hair cells, immunolocalization of Ctbp2 showed fewer ribbon-containing cells in total and an altered distribution of Ctbp2 puncta compared to wild-type hair cells. myo7aa−/− mutants have fewer postsynaptic densities – as assessed by MAGUK immunolabeling – compared to wild-type zebrafish. We quantified the circular swimming behavior of myo7aa−/− mutant fish and measured a greater turning angle (absolute smooth orientation). It has previously been shown that L-type voltage-gated calcium channels are necessary for ribbon localization and occurrence of postsynaptic density; thus, we hypothesized and observed that L-type voltage-gated calcium channel agonists change behavioral and synaptic phenotypes in myo7aa−/− mutants in a drug-specific manner. Our results indicate that treatment with L-type voltage-gated calcium channel agonists alter hair cell synaptic elements and improve behavioral phenotypes of myo7aa−/− mutants. Our data support that L-type voltage-gated calcium channel agonists induce morphological changes at the ribbon synapse – in both the number of tethered vesicles and regarding the distribution of Ctbp2 puncta – shift swimming behavior and improve acoustic startle response.

Purpose Hearing loss is a common impairment of the human senses with an estimated 48 million American adults reporting some trouble hearing; however, access to hearing health care is limited. Detection of hearing loss through a mobile, handheld tool can provide an important access point and potentially expedited access to the continuum of hearing health care. Here, we determined that GoAudio, a portable, automated hearing assessment tool, can be used to identify individuals who require additional hearing evaluation in a clinical workflow. Method This initial study included 24 adults, ages 18–65 years ( M = 50, SD = 12), tested with GoAudio versus “gold-standard” clinical audiometry for eight frequencies to evaluate “real-world” applications. Participants utilized noise-canceling headphones combined with a tablet-based application for the GoAudio assessment. Results The primary study outcome measurements were the comparison of hearing thresholds (dB HL) from clinical audiometry and GoAudio. Results suggest that GoAudio is comparable to clinical audiometry for the identification of hearing loss at most frequencies (except 1 kHz for both ears and 2 kHz in the right ear). Upon stratifying data based on age, we identified that GoAudio is capable of identifying suspected age-related hearing loss or hearing thresholds greater than 30 dB HL at higher frequencies in both ears. Conclusion The study results support that GoAudio can be used effectively in clinical practice workflows as a reliable hearing assessment tool for the identification of hearing loss at the majority of frequencies outside a sound-treated booth and can detect characteristics of age-related hearing loss. Supplemental Material https://doi.org/10.23641/asha.13087682

PurposeMore than 460 million people are impacted by disabling hearing loss worldwide. Hearing loss has negative impacts across the life span and varies by individual. Specifically, in children, hearing loss has been shown to affect learning outcomes, behavioral and cognitive growth, and psychosocial development. In adults, hearing loss has been shown to affect quality of life, social isolation, depression, and anxiety. The purpose of this review is to advance the understanding of the latest research in the development of new treatments of hearing loss, including gene therapy, stem cell therapy, and pharmacotherapies. We address the use of animals to model human hearing loss and the importance of animals in previous discoveries and developing new therapies. We highlight the importance of early identification for better speech and developmental outcomes specifically in pediatric individuals. Lastly, we review new possibilities in the prevention of hearing loss and the path to translation into practice.ConclusionsResearch and development of new therapies to treat hearing loss is an ever growing field with many notable successes. However, clinical translation still poses many challenges. Many discoveries related to gene therapy, stem cell therapy, and pharmacotherapy are in the early phases of clinical trials and hold promise. This review empowers audiologists to be aware of these most recent developments and be conscious of the evolving future landscape of treatment and management of hearing loss.

PurposeMore than 460 million people suffer from disabling hearing loss worldwide, and about 50%–60% of hearing loss in infants are due to genetics. Usher syndrome is a genetic condition in which children are born deaf or hard of hearing and subsequently develop retinitis pigmentosa. It is the most common cause of deafness and blindness in pediatric populations, and pathogenic variants in 10 different genes are shown to be causative. The purpose of this review article is to advance the understanding of the clinical symptoms of an individual with Usher syndrome and highlight the latest research in the development of new treatments including gene therapy. The care and management of individuals with Usher syndrome require a team of multidisciplinary health care professionals, including an audiologist, a speech-language pathologist, an ophthalmologist, and a medical geneticist. We highlight the importance of early identification for better speech and developmental outcomes, specifically in pediatric individuals.ConclusionThis review empowers audiologists to be aware of early signs of Usher syndrome as they are typically the first point of contact and provides important information for audiologists and other health care professionals involved in the care of individuals with hearing loss and vision loss.