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Transcriptional changes in adhesion-related genes are site-specific during noise-induced cochlear pathogenesis.

ABSTRACT: Cell-cell junctions and junctions between cells and extracellular matrix are essential for maintenance of the structural and functional integrity of the cochlea, and are also a major target of acoustic trauma. While morphological assessments have revealed adhesion dysfunction in noise-traumatized cochleae, the molecular mechanisms responsible for adhesion disruption are not clear. Here, we screened the transcriptional expression of 49 adhesion-related genes in normal rat cochleae and measured the expression changes in the early phases of cochlear pathogenesis after acoustic trauma. We found that genes from four adhesion families, including the immunoglobulin superfamily and the integrin, cadherin, and selectin families, are expressed in the normal cochlea. Exposure to an intense noise at 120dB sound pressure level (SPL) for 2h caused site-specific changes in expression levels in the apical and the basal sections of the sensory epithelium. Expression changes that occurred in the cochlear sensory epithelium were biphasic, with early upregulation at 2h post-noise exposure and subsequent downregulation at 1day post-exposure. Importantly, the altered expression level of seven genes (Sgce, Sell, Itga5, Itgal, Selp, Cntn1 and Col5a1) is related to the level of threshold shift of the auditory brainstem response (ABR), an index reflecting functional change in the cochlea. Notably, the genes showing expression changes exhibited diverse constitutive expression levels and belong to multiple adhesion gene families. The finding of expression changes in multiple families of adhesion genes in a temporal fashion (2h vs. 1day) and a spatial fashion (the apical and the basal sensory epithelia as well as the lateral wall tissue) suggests that acoustic overstimulation provokes a complex response in adhesion genes, which likely involves multiple adhesion-related signaling pathways.

SUBMITTER: Cai Q

PROVIDER: S-EPMC3259216 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Transcriptional changes in adhesion-related genes are site-specific during noise-induced cochlear pathogenesis.

Cai Qunfeng Q Patel Minal M Coling Donald D Hu Bo Hua BH

Neurobiology of disease 20111025 2

Cell-cell junctions and junctions between cells and extracellular matrix are essential for maintenance of the structural and functional integrity of the cochlea, and are also a major target of acoustic trauma. While morphological assessments have revealed adhesion dysfunction in noise-traumatized cochleae, the molecular mechanisms responsible for adhesion disruption are not clear. Here, we screened the transcriptional expression of 49 adhesion-related genes in normal rat cochleae and measured th ...[more]

PMID: 22044737

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Project description:The molecular mechanisms underlying the great differences in susceptibility to noise-induced hearing loss (NIHL) exhibited by both humans and laboratory animals are unknown. Using microarray technology, the present study demonstrates that the effects of noise overexposure on the expression of molecules likely to be important to the development of NIHL differ among inbred mice that have distinctive susceptibilities to NIHL including B6.CAST, 129X1/SvJ, and 129S1/SvImJ. The noise-exposure protocol produced, on average, a permanent loss of about 40 dB in sensitivity for auditory brainstem responses in susceptible B6.CAST mice, but no threshold elevations for the two resistant 129S1/SvImJ and 129X1/SvJ substrains. Measurements of noise-induced gene expression changes 6 h after the noise exposure revealed significant alterations in the expression levels of 48 genes in the resistant mice, while by these same criteria, there were seven differentially expressed genes in the susceptible B6.CAST mice. Differentially expressed genes in both groups of mice included subsets of transcription factors. However, only in the resistant mice was there a significant induction of proteins involved in cell-survival pathways such as HSP70, HSP40, p21, GADD45ï¢, Ier3, and Nfï«ï¢iïº. Moreover, increased expression of three of these factors after noise was confirmed at the protein level. Drastically enhanced HSP70, GADD45ï¢, and p21 immunostaining were detected 6 h after the noise exposure in subsets of cells of the lateral wall, spiral limbus, and organ of Corti as well as in cochlear nerve fibers. Upregulation of these proteins after noise exposure likely contributes to the prevalence of survival cellular pathways and thus to the resistance to NIHL that is characteristic of the 129X1/SvJ mice. Experiment Overall Design: Female 10-wk-old mice of the B6.CAST and 129X1/SvJ strains were divided randomly into non-noise control and noise-exposure groups. The non-noise mice served as controls in the gene-profiling experiments to control for the stress induced by experimenter handling and/or confinement of the mice in the noise-exposure chamber that was not directly related to the noise. This mice were in the noise chamber for a sham exposure. In contrast, the ânoiseâ groups were exposed to a 105-dB SPL, 10-kHz octave band of noise for 1 h and sacrificed 6 h after the exposure. Of each of these major groups, eight mice were used for each of three 129X1/SvJ control and three noise-exposed 129X1/SvJ arrays and two B6.CAST control and two noise-exposed B6.CAST arrays. Consequently within each subgroup the arrays are biological replicates.

Project description:Noise-induced hearing loss has gained relevance as one of the most common forms of hearing impairment. The anatomical correlates of hearing loss, principally cell damage and/or death, are relatively well-understood histologically. However, much less is known about the physiological aspects of damaged, surviving cells. Here we addressed the functional consequences of noise exposure on the capacity of inner hair cells (IHCs) to release synaptic vesicles at synapses with spiral ganglion neurons (SGNs). Mice of either sex at postnatal day (P) 15-16 were exposed to 1-12 kHz noise at 120 dB sound pressure level (SPL), for 1 h. Exocytosis was measured by tracking changes in membrane capacitance (ΔCm) from IHCs of the apical cochlea. Upon IHC depolarization to different membrane potentials, ΔC m showed the typical bell-shaped curve that mirrors the voltage dependence of Ca2+ influx, in both exposed and unexposed cells. Surprisingly, from IHCs at 1-day after exposure (d.a.e.), we found potentiation of exocytosis at the peak of the bell-shaped curve. The increase in exocytosis was not accompanied by changes in whole-cell Ca2+ influx, suggesting a modification in coupling between Ca2+ channels and synaptic vesicles. Consistent with this notion, noise exposure also changed the Ca2+-dependence of exocytosis from linear to supralinear. Noise exposure did not cause loss of IHCs, but did result in a small reduction in the number of IHC-SGN synapses at 1-d.a.e. which recovered by 14-d.a.e. In contrast, a strong reduction in auditory brainstem response wave-I amplitude (representing synchronous firing of SGNs) and distortion product otoacoustic emissions (reflecting outer hair cell function) indicated a profound hearing loss at 1- and 14-d.a.e. To determine the role of glutamate release in the noise-induced potentiation of exocytosis, we evaluated vesicular glutamate transporter-3 (Vglut3) knock-out (KO) mice. Unlike WT, IHCs from Vglut3 KO mice showed a noise-induced reduction in ΔC m and Ca2+ influx with no change in the Ca2+-dependence of exocytosis. Together, these results indicate that traumatic noise exposure triggers changes of IHC synaptic function including a Vglut3-dependent potentiation of exocytosis.

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Transcriptional changes in adhesion-related genes are site-specific during noise-induced cochlear pathogenesis.

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Transcriptional changes in adhesion-related genes are site-specific during noise-induced cochlear pathogenesis.

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