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.1998 Dec 22;95(26):15758-62.
doi: 10.1073/pnas.95.26.15758.

Thyroid hormone receptor beta-dependent expression of a potassium conductance in inner hair cells at the onset of hearing

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Thyroid hormone receptor beta-dependent expression of a potassium conductance in inner hair cells at the onset of hearing

A Rüsch et al. Proc Natl Acad Sci U S A..

Abstract

To elucidate the role of thyroid hormone receptors (TRs) alpha1 and beta in the development of hearing, cochlear functions have been investigated in mice lacking TRalpha1 or TRbeta. TRs are ligand-dependent transcription factors expressed in the developing organ of Corti, and loss of TRbeta is known to impair hearing in mice and in humans. Here, TRalpha1-deficient (TRalpha1(-/-)) mice are shown to display a normal auditory-evoked brainstem response, indicating that only TRbeta, and not TRalpha1, is essential for hearing. Because cochlear morphology was normal in TRbeta-/- mice, we postulated that TRbeta regulates functional rather than morphological development of the cochlea. At the onset of hearing, inner hair cells (IHCs) in wild-type mice express a fast-activating potassium conductance, IK,f, that transforms the immature IHC from a regenerative, spiking pacemaker to a high-frequency signal transmitter. Expression of IK,f was significantly retarded in TRbeta-/- mice, whereas the development of the endocochlear potential and other cochlear functions, including mechanoelectrical transduction in hair cells, progressed normally. TRalpha1(-/-) mice expressed IK,f normally, in accord with their normal auditory-evoked brainstem response. These results establish that the physiological differentiation of IHCs depends on a TRbeta-mediated pathway. When defective, this may contribute to deafness in congenital thyroid diseases.

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Figures

Figure 1
Figure 1
Auditory-evoked brainstem responses in TRα1- and TRβ-deficient mice. Columns indicate mean ABR thresholds ± SEM in dB sound pressure level for click, 8-, 16-, and 32-kHz frequency stimuli. Thresholds of TRα1−/− mice were not significantly different from wt mice, whereas TRβ−/− mice have significantly elevated thresholds over TRβ+/+ or TRβ−/+ mice (∗∗,P < 0.01; ref. 15). Numbers of mice per group:n = 4, TRβ−/+;n = 9, TRβ−/−;n = 6, TRα1+/+;n = 8, TRα1−/−. TRβ−/− and TRα1−/− mice were compared with control mice (TRβ−/+ and TRα1+/+, respectively) of the corresponding genetic backgrounds (seeMaterials and Methods).
Figure 2
Figure 2
Acutely isolated organ of Corti of a P18 wt mouse prepared for IHC recordings. (A) A section of the organ of Corti isolated from the basal region of the cochlea observed from the site of the stria vascularis. The short stereocilia of hair bundles of the IHCs are visible at the top. Pillar cells (PCs) rigidly couple IHCs to the OHCs, here seen at the level of their nuclei. (B) The same IHCs seen inA after OHCs and pillar cells have been removed mechanically with micropipettes. (C) IHC during the whole-cell voltage-clamp recording. A patch pipette has been sealed onto its cleaned basolateral surface while the cell remains inside the semiintact sensory epithelium of the organ of Corti.
Figure 3
Figure 3
Whole-cell membrane currents of IHCs. (A) At P18, IHCs of wt and TRα1−/− mice expressed an additional, fast-activating K+ current,IK,f, that was absent in TRβ−/− mice. The very large membrane currents in the TRα1−/− cell at P18 caused a less effective voltage clamp of the membrane potential and a rounded-looking onset of the largest current traces shown. This very large current is not the result of a physiological difference, as it was not seen with smaller series resistances or smaller total membrane currents in other cells. The TRα1−/− recording denoted at P10 was derived from a cell at P13 not yet expressing the fast current component. (B) In adult animals, membrane currents are similar in IHCs of wt and TRβ−/− mice. (C)IK,f at −25 mV, measured at the points indicated by bars and arrows inA, as a function of the day of postnatal development. Curves representIK,f in TRα1−/− and wt (solid line) and TRβ−/− (dotted line) mice. Individual points represent wt (♦), TRα1−/− (∗) and TRβ−/− mice (• and ○, apical and basal turn of cochlea, respectively). Fits are according to Eq.[1].Imin (−208 pA) was determined by the IHCs’ Ca2+ currents. In mice older than about P40,Imax (4.26 and 3.14 nA in wt and TRβ−/− mice, respectively) was not significantly different (P > 0.05) in the two fits, based on the cells’ membrane capacitances, when data were expressed in current densities (nA/pF).
Figure 4
Figure 4
Normal physiology of immature cochlear hair cells in TRβ−/− mice. (A andB) When stimulated by a fluid jet at −84 mV, IHCs and OHCs of TRβ−/− mice responded with mechanoelectrical transducer currents, as found in wt cells. Currents were half-blocked by ≈3 μMd-tubocurarine as described for wt CD1 mice (22). (C andD) IHCs of TRβ−/− and wt mice responded similarly to current injections by forming slow Ca2+ action potentials. The TRβ−/− cell was slightly more depolarized and had a smaller input resistance than the wt cell (300 and 1,000 MΩ, respectively), effecting a faster membrane time constant and a more noisy-looking voltage response. For the same reason, the 20-pA current injection was less effective in the TRβ−/− cell in depolarizing the cell membrane, initiating only three action potentials. Other TRβ−/− cells had higher input resistances comparable to wt cells. (E andF) Voltage-dependent capacitance of OHCs in wt and TRβ−/− mice. Acutely isolated OHCs of apical turns at P8. Capacitances were normalized to accomodate differences in cell size by dividing by the cells’ linear, voltage-independent capacitances. We assume that observed differences in capacitance in TRβ−/− mice at P8 are not functionally significant.
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