Deafness and Permanently Reduced Potassium Channel Gene Expression and Function in HypothyroidPit1dwMutants
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Abstract:
The absence of thyroid hormone (TH) during late gestation and early infancy can cause irreparable deafness in both humans and rodents. A variety of rodent models have been used in an effort to identify the underlying molecular mechanism. Here, we characterize a mouse model of secondary hypothyroidism, pituitary transcription factor 1 ( Pit1 dw ), which has profound, congenital deafness that is rescued by oral TH replacement. These mutants have tectorial membrane abnormalities, including a prominent Hensen's stripe, elevated β-tectorin composition, and disrupted striated-sheet matrix. They lack distortion product otoacoustic emissions and cochlear microphonic responses, and exhibit reduced endocochlear potentials, suggesting defects in outer hair cell function and potassium recycling. Auditory system and hair cell physiology, histology, and anatomy studies reveal novel defects of hormone deficiency related to deafness: (1) permanently impaired expression of KCNJ10 in the stria vascularis of Pit1 dw mice, which likely contributes to the reduced endocochlear potential, (2) significant outer hair cell loss in the mutants, which may result from cellular stress induced by the lower KCNQ4 expression and current levels in Pit1 dw mutant outer hair cells, and (3) sensory and strial cell deterioration, which may have implications for thyroid hormone dysregulation in age-related hearing impairment. In summary, we suggest that these defects in outer hair cell and strial cell function are important contributors to the hearing impairment in Pit1 dw mice.Keywords:
Endocochlear potential
The influence to endocochlear potential (EP), cochlear microphonics (CM) and summating potential (SP), the ultrastructural changes of the cochlea and the survival time of hair cells in guinea pigs during anoxia and suffocation were investigated. We found that: 1) The stria vascularis was much more sensitive to anoxia than hair cells. 2) 85% CM was highly sensitive to anoxia, and 15% kept stable until the destruction of outer hair cells. 3) -SP turned into +SP after anoxia. 4) EP was related to the destruction of outer hair cells and the disappearance of CM.
Endocochlear potential
Kinocilium
Microphonics
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Bromodeoxyuridine
Ototoxicity
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Research in mammalian hair cell regeneration is hampered by a lack of in vivo model of adult mouse inner ear injury. In the present study we investigated the effects of a combination of a single dose of aminoglycoside followed by a loop diuretic in adult mice. The auditory brainstem response threshold shift, extent and defining characteristics of the cochlear lesion were assessed and verified at different time points post-treatment. Our data indicated that this drug combination caused the rapid and extensive death of outer hair cells (OHCs). OHC death presented throughout the cochlea that commenced in the basal turn by 24 h and progressed apically. In contrast, inner hair cell (IHC) loss was delayed and mild. Terminal deoxynucleotidyl transferase dUTP nick end labelling-positive nuclei demonstrated that the majority of OHCs died via an apoptotic pathway. Auditory threshold shifts of up to 90 dB SPL indicated a profound hearing loss. In addition, the endocochlear potential (EP) in the drug-treated animals displayed a significant decline at 12 h post-treatment followed by recovery by 48 h post-treatment. Despite this recovery, there was a significant and progressive decrease in strial vascularis thickness, which was predominantly due to atrophy of marginal cells. The present study reproduced an adult mouse model of aminoglycoside-induced hearing loss. The mechanism underlying the recovered EP in the model with extensive hair cell death is discussed.
Endocochlear potential
Auditory brainstem response
Ototoxicity
Terminal deoxynucleotidyl transferase
Round window
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Abstract Here we present spatio-temporal localization of Kremen1, a transmembrane receptor, in the mammalian cochlea and investigate its role in the formation of sensory organs in mammal and fish model organisms. We show that Kremen1 is expressed in prosensory cells during cochlear development and in supporting cells of the adult mouse cochlea. Based on this expression pattern, we investigated whether Kremen1 functions to modulate cell fate decisions in the prosensory domain of the developing cochlea. We used gain and loss-of-function experiments to show that Kremen1 is sufficient to bias cells towards supporting cell fate and is implicated in suppression of hair cell formation. In addition to our findings in the mouse cochlea, we examined the effects of over expression and loss of Kremen1 in the zebrafish lateral line. In agreement with our mouse data, we show that over expression of Kremen1 has a negative effect on the number of mechanosensory cells that form in the zebrafish neuromasts and that fish lacking Kremen1 protein develop more hair cells per neuromast compared to wild type fish. Collectively, these data support an inhibitory role for Kremen1 in hair cell fate specification.
Lateral line
Cell fate determination
Cell type
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Endocochlear potential
Cochlear duct
Endolymph
Microphonics
Receptor potential
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Objectives: Our study aims to determine the immunostaining pattern of Kir4.1 channels in human cochlear tissues. Potassium recycling pathways critical for maintaining cochlear ion homeostasis and the endocochlear potential have been defined largely in animal models. Potassium effluxed from sensory hair cells is taken up by supporting cells and returned to the stria vascularis via two distinct transcellular syncytial networks consisting of epithelial cells and spiral ligament fibrocytes. The inward rectifying potassium channel Kir4.1 appears to be an essential component of this process, as evidenced by murine knockout models lacking an endocochlear potential. Animal models have demonstrated robust Kir4.1 expression in several cell types along the cochlear potassium recycling pathway. However, Kir4.1 immunostaining patterns in the human cochlea remain undefined. Methods: Postmortem human temporal bones were collected through the Hearing Research Program at the Medical University of South Carolina. Temporal bones were fixed within 6 to 11 hours of death and underwent microwave decalcification prior to immunohistochemical staining for Kir4.1. Results: Robust Kir4.1 immunoreactivity was present in strial intermediate cells, outer sulcus root processes and glial cells in Rosenthal's canal. The distribution of Kir4.1 in the human cochlea was generally similar to that reported in animal models. Conclusions: Our findings suggest that Kir4.1 channels play a critical role in the regulation of potassium recirculation in the human cochlea. Further immunohistochemical analyses are necessary to fully delineate the precise location of Kir4.1 in the complex potassium recycling pathway and elucidate its potential role in lateral wall degeneration and associated hearing loss.
Endocochlear potential
Spiral ligament
Immunostaining
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ABSTRACT The mammalian hearing organ, the cochlea, contains an active amplifier to boost the vibrational response to low level sounds. Hallmarks of this active process are sharp location-dependent frequency tuning and compressive nonlinearity over a wide stimulus range. The amplifier relies on outer hair cell (OHC) generated forces driven in part by the endocochlear potential (EP), the ~ +80 mV potential maintained in scala media, generated by the stria vascularis. We transiently eliminated the EP in vivo by an intravenous injection of furosemide and measured the vibrations of different layers in the cochlea’s organ of Corti using optical coherence tomography. Distortion product otoacoustic emissions (DPOAE) were monitored at the same times. Following the injection, the vibrations of the basilar membrane lost the best frequency (BF) peak and showed broad tuning similar to a passive cochlea. The intra-organ of Corti vibrations measured in the region of the OHCs lost their BF peak and showed low-pass responses, but retained nonlinearity, indicating that OHC electromotility was still operational. Thus, while electromotility is presumably necessary for amplification, its presence is not sufficient for amplification. The BF peak recovered nearly fully within 2 hours, along with a non-monotonic DPOAE recovery that suggests that physical shifts in operating condition are a final step in the recovery process. SIGNIFICANCE The endocochlear potential, the +80 mV potential difference across the fluid filled compartments of the cochlea, is essential for normal mechanoelectrical transduction, which leads to receptor potentials in the sensory hair cells when they vibrate in response to sound. Intracochlear vibrations are boosted tremendously by an active nonlinear feedback process that endows the cochlea with its healthy sensitivity and frequency resolution. When the endocochlear potential was reduced by an injection of furosemide, the basilar membrane vibrations resembled those of a passive cochlea, with broad tuning and linear scaling. The vibrations in the region of the outer hair cells also lost the tuned peak, but retained nonlinearity at frequencies below the peak, and these sub-BF responses recovered fairly rapidly. Vibration responses at the peak recovered nearly fully over 2 hours. The staged vibration recovery and a similarly staged DPOAE recovery suggests that physical shifts in operating condition are a final step in the process of cochlear recovery.
Endocochlear potential
Basilar membrane
Receptor potential
Endolymph
Cochlear duct
Otoacoustic emission
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Abstract Pannexin1 (Panx1) is a gap junction gene in vertebrates whose proteins mainly function as non-junctional channels on the cell surface. Panx1 channels can release ATP under physiological conditions and play critical roles in many physiological and pathological processes. Here, we report that Panx1 deficiency can reduce ATP release and endocochlear potential (EP) generation in the cochlea inducing hearing loss. Panx1 extensively expresses in the cochlea, including the cochlear lateral wall. We found that deletion of Panx1 in the cochlear lateral wall almost abolished ATP release under physiological conditions. Positive EP is a driving force for current through hair cells to produce auditory receptor potential. EP generation requires ATP. In the Panx1 deficient mice, EP and auditory receptor potential as measured by cochlear microphonics (CM) were significantly reduced. However, no apparent hair cell loss was detected. Moreover, defect of connexin hemichannels by deletion of connexin26 (Cx26) and Cx30, which are predominant connexin isoforms in the cochlea, did not reduce ATP release under physiological conditions. These data demonstrate that Panx1 channels dominate ATP release in the cochlea ensuring EP and auditory receptor potential generation and hearing. Panx1 deficiency can reduce ATP release and EP generation causing hearing loss.
Endocochlear potential
Receptor potential
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Normal cochlear function depends on maintaining the correct ionic environment for the sensory hair cells. Here we review recent literature on the cellular distribution of potassium transport-related molecules in the cochlea.Transgenic animal models have identified novel molecules essential for normal hearing and support the idea that potassium is recycled in the cochlea. The findings indicate that extracellular potassium released by outer hair cells into the space of Nuel is taken up by supporting cells, that the gap junction system in the organ of Corti is involved in potassium handling in the cochlea, that the gap junction system in stria vascularis is essential for the generation of the endocochlear potential, and that computational models can assist in the interpretation of the systems biology of hearing and integrate the molecular, electrical, and mechanical networks of the cochlear partition. Such models suggest that outer hair cell electromotility can amplify over a much broader frequency range than expected from isolated cell studies.These new findings clarify the role of endolymphatic potassium in normal cochlear function. They also help current understanding of the mechanisms of certain forms of hereditary hearing loss.
Endocochlear potential
Prestin
Cochlear duct
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