Mice heterozygous for the Cdh23/Ahl1 mutation show age-related deficits in auditory temporal processing

Burghard, A; N, Morel; Oliver, Douglas L.

doi:10.1016/j.neurobiolaging.2019.02.029

Cited by 14 publications

(14 citation statements)

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“…To examine the auditory thresholds at specific frequencies of sound, audiograms were obtained by recording amplitude modulation following responses (AMFR). The AMFR is an electrophysiological response that is more sensitive and frequency-specific than the ABR, and is not reliant on any subjective evaluation [ 51 , 52 ]. The recorded audiograms revealed no differences between genotypes ( Fig 4B ).…”

Section: Resultsmentioning

confidence: 99%

“…The same open field speaker arrangement and electrode placement were used as described above. The general amplitude-modulated frequency response principle is described in [ 50 , 51 ] and performed herein as described in [ 52 ]. In brief, the detection is based on the magnitude squared coherence (MSC) algorithm calculated with modulation sounds and the recorded responses of the electrical potential produced by the brain.…”

Section: Methodsmentioning

confidence: 99%

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C1ql1 is expressed in adult outer hair cells of the cochlea in a tonotopic gradient

et al. 2021

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Hearing depends on the transduction of sounds into neural signals by the inner hair cells of the cochlea. Cochleae also have outer hair cells with unique electromotile properties that increase auditory sensitivity, but they are particularly susceptible to damage by intense noise exposure, ototoxic drugs, and aging. Although the outer hair cells have synapses on afferent neurons that project to the brain, the function of this neuronal circuit is unclear. Here, we created a novel mouse allele that inserts a fluorescent reporter at the C1ql1 locus which revealed gene expression in the outer hair cells and allowed creation of outer hair cell-specific C1ql1 knockout mice. We found that C1ql1 expression in outer hair cells corresponds to areas with the most sensitive frequencies of the mouse audiogram, and that it has an unexpected adolescence-onset developmental timing. No expression was observed in the inner hair cells. Since C1QL1 in the brain is made by neurons, transported anterogradely in axons, and functions in the synaptic cleft, C1QL1 may serve a similar function at the outer hair cell afferent synapse. Histological analyses revealed that C1ql1 conditional knockout cochleae may have reduced outer hair cell afferent synapse maintenance. However, auditory behavioral and physiological assays did not reveal a compelling phenotype. Nonetheless, this study identifies a potentially useful gene expressed in the cochlea and opens the door for future studies aimed at elucidating the function of C1QL1 and the function of the outer hair cell and its afferent neurons.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

C1ql1 is expressed in adult outer hair cells of the cochlea in a tonotopic gradient

et al. 2021

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“…CBA/CaJ mice are homozygous for the wild-type Cdh23 gene and maintain normal hearing through their lifespan. A single copy of the wild type Cdh23 allele is sufficient for normal auditory processing until at least one year of age (Frisina et al, 2011;Burghard et al, 2019;Lyngholm and Sakata, 2019).…”

Section: Resultsmentioning

confidence: 99%

Group II Metabotropic Glutamate Receptors Modulate Sound Evoked and Spontaneous Activity in the Mouse Inferior Colliculus

Kristaponyte

Beebe

Young

et al. 2020

eNeuro

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Little is known about the functions of group II metabotropic glutamate receptors (mGluRs2/3) in the inferior colliculus (IC)-a midbrain structure that is a major integration region of the central auditory system. We investigated how these receptors modulate sound-evoked and spontaneous firing in the mouse IC in vivo. We first performed immunostaining and tested hearing thresholds to validate VGAT-ChR2 transgenic mice on a mixed CBA/CaJ x C57BL/6J genetic background. Transgenic animals allowed for optogenetic cell type identification. Extracellular single neuron recordings were obtained before and after pharmacological mGluR2/3 activation. We observed increased sound-evoked firing-as assessed by the rate-level functions-in a subset of both GABAergic and non-GABAergic IC neurons following mGluR2/3 pharmacological activation. These neurons also displayed elevated spontaneous excitability and were distributed throughout the IC area tested, suggesting a widespread mGluR2/3 distribution in the mouse IC. SignificanceGlutamate is the primary excitatory neurotransmitter in the brain. It binds to both ionotropic and metabotropic glutamate receptors. Fast ionotropic receptors generate rapid synaptic transmission, whereas slower metabotropic glutamate receptors (mGluRs) modulate this synaptic transmission. Here, we discovered that activation of group II mGluRs enhances sound-evoked and spontaneous neuronal firing in the inferior colliculus-the hub of the central auditory system. We used transgenic mice which allowed for identification of excitatory and inhibitory neurons and found that both these cell types are modulated by group II mGluRs. Our results provide better understanding of mGluR modulatory roles, which is crucial in opening avenues for using mGluR-targeting drugs to treat hearing Glutamate is the primary excitatory neurotransmitter in the brain. It binds to both ionotropic and metabotropic glutamate receptors (mGluRs). Ionotropic receptors, which are ligand-gated cation channels, are important for rapid signal transmission, whereas mGluRs act via G-protein coupled second messenger cascades and are relatively slower. In general, mGluRs have been thoroughly investigated due to their potential as therapeutic targets in several psychiatric and neurological disorders

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“…We also show that the B6.cdh23 +/mice have comparable high-frequency SC response to the CBA/CaJ mice, but only partially restored topographic maps. Others have also shown that the C57BL/6 mice heterozygous for the Cdh23/Ahl1 mutation show age-related deficits in auditory temporal processing (Burghard et al, 2019). Furthermore, since both F1(CBA/CaJ x C57BL/6) and B6.cdh23 +/are heterozygous for the Cdh23 mutation, we speculate that the reason for the absence of a complete restoration might be that C57BL/6 mice harbor other mutations outside of Cdh23 that affect high-frequency hearing, as has been reviewed (Bowl & Dawson, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that this rescues the age-related hearing deficit of C57BL/6 mice (Firisnia et al 2001, (Lyngholm & Sakata, 2019), demonstrating that it is recessive alleles carried by the C57BL/6 mice that lead to deafness. The auditory deficits of C57BL/6 mice can also at least be partially restored by changing the C57BL/6 mutant Cdh23 allele with the wildtype allele using CRISPR (Mianné et al, 2016), although one report suggested that hearing is only partially restored in this mouse line (Burghard et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

High-frequency hearing is required for generating a topographic map of auditory space in the mouse superior colliculus

Si¹,

Ito

Litke³

et al. 2021

Preprint

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A topographic map of auditory space is a feature found in the superior colliculus (SC) of many species, including CBA/CaJ mice. In this genetic background, high-frequency monaural spectral cues and interaural level differences are used to generate spatial receptive fields (RFs) that form a topographic map along the azimuth. Unfortunately, C57BL/6 mice, a strain widely used for transgenic manipulation, display age-related hearing loss (AHL) due to an inbred mutation in the Cadherin 23 gene (Cdh23) that affects hair cell mechanotransduction. To overcome this problem, researchers have used young C57BL/6 mice in their studies, as they have been shown to have normal hearing thresholds. However, important details of the auditory response characteristics of the SC such as spectral responses and spatial localization, have not been characterized in young C57BL/6 mice.Here we show that 2-4-month C57BL/6 mice lack neurons with frontal auditory RFs and therefore lack a topographic representation of auditory space in the SC. Analysis of the spectrotemporal receptive fields (STRFs) of the SC auditory neurons shows that C57BL/6 mouse SC neurons lack the ability to detect the high-frequency (>40kHz) spectral cues that are needed to compute frontal RFs. We also show that crossing C57BL/6 mice with CBA/CaJ mice or introducing one copy of the wild-type Cdh23 to C57BL/6 mice rescues the high-frequency hearing deficit and improves the topographic map of auditory space. Taken together, these results demonstrate the importance of high-frequency hearing in computing a topographic map of auditory space.Significance StatementDespite the strain’s age-dependent hearing loss, C57BL/6 mice are widely used in auditory studies because of the development of transgenic reporter and Cre lines in this genetic background. Here we examined the topographic map of auditory space and spectrotemporal properties of neurons in the SC of C57BL/6 mice. We found an early-onset high-frequency hearing deficit that results in the loss of SC neurons with frontal RFs and, consequently, an absence of a topographic map of auditory space. These findings stress the importance of high-frequency hearing in generating spatially restricted receptive fields and serve as a caution to researchers that doing auditory-related research using the C57BL/6 genetic background may not be representative of true wild-type mice.

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Mice heterozygous for the Cdh23/Ahl1 mutation show age-related deficits in auditory temporal processing

Cited by 14 publications

References 46 publications

C1ql1 is expressed in adult outer hair cells of the cochlea in a tonotopic gradient

C1ql1 is expressed in adult outer hair cells of the cochlea in a tonotopic gradient

Group II Metabotropic Glutamate Receptors Modulate Sound Evoked and Spontaneous Activity in the Mouse Inferior Colliculus

High-frequency hearing is required for generating a topographic map of auditory space in the mouse superior colliculus

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