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?2?3 is essential for normal structure and function of auditory nerve synapses and is a novel candidate for auditory processing disorders.

ABSTRACT: The auxiliary subunit ?2?3 modulates the expression and function of voltage-gated calcium channels. Here we show that ?2?3 mRNA is expressed in spiral ganglion neurons and auditory brainstem nuclei and that the protein is required for normal acoustic responses. Genetic deletion of ?2?3 led to impaired auditory processing, with reduced acoustic startle and distorted auditory brainstem responses. ?2?3(-/-) mice learned to discriminate pure tones, but they failed to discriminate temporally structured amplitude-modulated tones. Light and electron microscopy analyses revealed reduced levels of presynaptic Ca(2+) channels and smaller auditory nerve fiber terminals contacting cochlear nucleus bushy cells. Juxtacellular in vivo recordings of sound-evoked activity in ?2?3(-/-) mice demonstrated impaired transmission at these synapses. Together, our results identify a novel role for the ?2?3 auxiliary subunit in the structure and function of specific synapses in the mammalian auditory pathway and in auditory processing disorders.

SUBMITTER: Pirone A

PROVIDER: S-EPMC6608152 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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α2δ3 is essential for normal structure and function of auditory nerve synapses and is a novel candidate for auditory processing disorders.

Pirone Antonella A Kurt Simone S Zuccotti Annalisa A Rüttiger Lukas L Pilz Peter P Brown David H DH Franz Christoph C Schweizer Michaela M Rust Marco B MB Rübsamen Rudolf R Friauf Eckhard E Knipper Marlies M Engel Jutta J

The Journal of neuroscience : the official journal of the Society for Neuroscience 20140101 2

The auxiliary subunit α2δ3 modulates the expression and function of voltage-gated calcium channels. Here we show that α2δ3 mRNA is expressed in spiral ganglion neurons and auditory brainstem nuclei and that the protein is required for normal acoustic responses. Genetic deletion of α2δ3 led to impaired auditory processing, with reduced acoustic startle and distorted auditory brainstem responses. α2δ3(-/-) mice learned to discriminate pure tones, but they failed to discriminate temporally structur ...[more]

PMID: 24403143

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Project description:ObjectivesTo determine whether suprathreshold measures of auditory function, such as distortion-product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABRs), are correlated with noise exposure history in normal-hearing human ears. Recent data from animal studies have revealed significant deafferentation of auditory nerve fibers after full recovery from temporary noise-induced hearing loss. Furthermore, these data report smaller ABR wave I amplitudes in noise-exposed animal ears when compared with non-noise-exposed control animals or prenoise exposure amplitudes in the same animal. It is unknown whether a similar phenomenon exists in the normal-hearing, noise-exposed human ear.DesignThirty normal-hearing human subjects with a range of noise exposure backgrounds (NEBs) participated in this study. NEB was quantified by the use of a noise exposure questionnaire that extensively queried loud sound exposure during the previous 12 months. DPOAEs were collected at three f2s (1, 2, and 4 kHz) over a range of L2s. DPOAE stimulus level began at 80 dB forward-pressure level and decreased in 10 dB steps. Two-channel ABRs were collected in response to click stimuli and 4 kHz tone bursts; one channel used an ipsilateral mastoid electrode and the other an ipsilateral tympanic membrane electrode. ABR stimulus level began at 90 dB nHL and was decreased in 10 dB steps. Amplitudes of waves I and V of the ABR were analyzed.ResultsA statistically significant relationship between ABR wave I amplitude and NEB was found for clicked-evoked ABRs recorded at a stimulus level of 90 dB nHL using a mastoid recording electrode. For this condition, ABR wave I amplitudes decreased as a function of NEB. Similar systematic trends were present for ABRs collected in response to clicks and 4 kHz tone bursts at additional suprathreshold stimulation levels (≥70 dB nHL). The relationship weakened and disappeared with decreases in stimulation level (≤60 dB nHL). Similar patterns were present for ABRs collected using a tympanic membrane electrode. However, these relationships were not statistically significant and were weaker and more variable than those collected using a mastoid electrode. In contrast to the findings for ABR wave I, wave V amplitude was not significantly related to NEB. Furthermore, there was no evidence of a systematic relationship between suprathreshold DPOAEs and NEB.ConclusionsA systematic trend of smaller ABR wave I amplitudes was found in normal-hearing human ears with greater amounts of voluntary NEB in response to suprathreshold clicks and 4 kHz tone bursts. These findings are consistent with the data from previous work completed in animals, where the reduction in suprathreshold responses was a result of deafferentation of high-threshold/low-spontaneous rate auditory nerve fibers. These data suggest that a similar mechanism might be operating in human ears after exposure to high sound levels. However, evidence of this damage is only apparent when examining suprathreshold wave I amplitude of the ABR. In contrast, suprathreshold DPOAE level was not significantly related to NEB. This was expected, given noise-induced auditory damage findings in animal ears did not extend to the outer hair cells, the generator for the DPOAE response.

Project description:Background:Some children appear to not hear well in class despite normal hearing sensitivity. These children may be referred for auditory processing disorder (APD) assessment but can also have attention, language, and/or reading disorders. Despite presenting with similar concerns regarding hearing difficulties in difficult listening conditions, the overall profile of deficits can vary in children with suspected or confirmed APD. The current study used cluster analysis to determine whether subprofiles of difficulties could be identified within a cohort of children presenting for auditory processing assessment. Methods:Ninety school-aged children (7-13 years old) with suspected APDs were included in a cluster analysis. All children had their reading, language, cognition and auditory processing assessed. Parents also completed the Children's Auditory Performance Scale (CHAPS). Cluster analysis was based on tasks where age-norms were available, including word reading (Castles and Coltheart irregular and non-words test), phonological awareness (Queensland University Inventory of Literacy), language [Comprehensive Language of Assessment-4, Comprehensive Assessment of Spoken Language (CASL)], sustained attention (Continuous Performance Test), working memory (digits forward and backward), and auditory processing [Frequency Pattern Test (FPT), Dichotic Digits Test (DDT)]. Hierarchical cluster analysis was undertaken to determine the optimal number of clusters for the data, followed by a k-means cluster analysis. Results:Hierarchical cluster analysis suggested a four-group solution. The four subgroups can be summarized as follows: children with (1) global deficits, n = 35; (2) poor auditory processing with good word reading and phonological awareness skills, n = 22; (3) poor auditory processing with poor attention and memory but good language skills, n = 15; and (4) poor auditory processing and attention with good memory skills, n = 18. Conclusion:The cluster analysis identified distinct subgroups of children. These subgroups display the variation in areas of difficulty observed across different studies in the literature (e.g., not every child with APD has an attention deficit), highlighting the heterogeneous nature of APD and the need to assess a range of skills in children with suspected APD. It would be valuable for future studies to independently verify these subgroups and to determine whether interventions can be optimized based on these subgroups.

Project description:Spiral ganglion neurons (SGNs) and the associated components of the auditory nerve are primary carriers of auditory information from hair cells to the brain. Loss of SGNs occurs with many pathological conditions, resulting in permanent sensorineural hearing loss. Neural stem/progenitors (NSPs) have been well-characterized in several locations of adult brain and retina. However, it is unclear whether NSPs are present in the adult auditory nerve. Here we examined the self-renewal potential of the adult auditory nerve using ouabain application as a well-established mouse model of acute SGN injury. The observed increase in cell proliferation, alteration in enchromatin/heterochromatin ratio and down-regulation of histone deacetylase expression in glial cells suggest that the quiescent glial cells convert to an activated state after SGN degeneration. This was further confirmed by global gene expression analysis of injured auditory nerves, which showed up-regulation of numerous neurogenesis- and/or development-associated genes shortly after ouabain exposure. These genes include molecular markers commonly used for the identification of NSPs. Under a strict culture regimen, auditory nerve-derived cells of adult mouse ears gave rise to neurospheres, suggesting that multipotent NSPs are present in adult cochlear nerve. Neurosphere assays on Sox2 transgenic mice revealed that Sox2+ glial cells are the source for NSPs. Our data also showed that acute injury or hypoxia enhances neurosphere formation. Taken together, our study revealed that glial cells of adult cochlea exhibit several NSP characteristics, and hence these mature non-neuronal cells may be important targets for promoting self-repair of degenerative auditory nerves. Auditory nerves were removed from the temporal bones of adult CBA/CaJ mice, aged 8 to 12 weeks. Tissues were either collected and used directly as the tissue samples or dissociated and used for the cell culture samples. Dissociated auditory nerve cells were propagated and grown to full confluency (5-7 days), constituting the cultured cell samples. For neurosphere samples, growth medium was changed to neurosphere formation medium and the cells were cultured for an additional 12 days. All samples were prepared in triplicate (n=3).

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?2?3 is essential for normal structure and function of auditory nerve synapses and is a novel candidate for auditory processing disorders.

Publications

α2δ3 is essential for normal structure and function of auditory nerve synapses and is a novel candidate for auditory processing disorders.

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