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1Department of Otology and Laryngology, Harvard Medical School and Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, 2Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee, and 3The Vollum Institute, Oregon Health Sciences University, Portland, Oregon
Submitted 7 November 2006; accepted in final form 25 January 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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9 and 10 in mediating suppressive effects of the olivocochlear efferent innervation. To probe the in vivo role of SK2 channels in hearing, we examined gene expression, cochlear function, efferent suppression, and noise vulnerability in mice overexpressing SK2 channels. Cochlear thresholds, as measured by auditory brain stem responses and otoacoustic emissions, were normal in overexpressers as was overall cochlear morphology and the size, number, and distribution of efferent terminals on outer hair cells. Cochlear expression levels of SK2 channels were elevated eightfold without striking changes in other SK channels or in the 9/10 nAChRs. Shock-evoked efferent suppression of cochlear responses was significantly enhanced in overexpresser mice as seen previously in 9 overexpresser mice; however, in contrast to 9 overexpressers, SK2 overexpressers were not protected from acoustic injury. Results suggest that efferent-mediated cochlear protection is mediated by other downstream effects of ACh-mediated Ca2+ entry different from those involving SK2-mediated hyperpolarization and the associated reduction in outer hair cell electromotility. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). The latter process, known as somatic electromotility, plays a key role in the amplification of cochlear motion and thus in the generation of responses at threshold sound levels (Dallos and Fakler 2002; Liberman et al. 2002). OHC function is regulated by the medial olivocochlear (MOC) efferent system, a sound-evoked negative feedback loop terminating on OHCs (Guinan 1996). Activation of this feedback system elevates cochlear thresholds and reduces the ear's vulnerability to acoustic injury (Kujawa and Liberman 1997).
The MOC/OHC synapse is cholinergic (Eybalin 1993). Studies of isolated hair cells suggest that ACh-gated Ca2+ entry through 9/10 nicotinic acetylcholine receptors (nAChRs) activate a hyperpolarizing current mediated by co-localized small-conductance Ca2+-activated K+ channels (SK2) (Elgoyhen et al. 1994; Elgoyhen et al. 2001; Fuchs and Murrow 1992; Oliver et al. 2000). In addition, ACh application decreases OHC stiffness via Ca2+-activated modification of OHC motor and/or cytoskeletal proteins (Dallos et al. 1997). Correspondingly, in vivo studies show that MOC activation elicits two types of suppression: a "fast" (
= 100 ms) effect thought to arise from OHC hyperpolarization, and a "slow" effect ( = 10 s) thought to arise from a wave of Ca2+-induced Ca2+ release propagating along the OHC basolateral membrane (Sridhar et al. 1997; Sridhar et al. 1995). Circumstantial evidence has suggested that the protective effects of shock-evoked MOC effects vis-à-vis acoustic vulnerability are mediated by slow rather than fast effects of ACh release (Reiter and Liberman 1995).
Gene targeting studies have begun to probe the roles of nAChRs and SK channels in the in vivo responses to MOC stimulation. Loss of 9 nAChR results in loss of fast and slow MOC-mediated suppression as well as subtle changes in the morphology of MOC terminals on OHCs (Vetter et al. 1999). Overexpression of 9AChR receptors results in enhanced MOC suppressive effects and renders the ear more resistant to acoustic injury (Maison et al. 2002). Deletion of SK2 channels also eliminates MOC-mediated suppression of cochlear responses, but also causes dramatic postnatal degeneration of MOC terminals which complicates interpretation of the loss of MOC function (Vetter et al. 2005).
Here, we study the effects of SK2 overexpression on inner ear function. SK2 overexpresser mice show enhanced MOC-evoked suppression without obvious changes in the distribution of efferent terminals in the OHC area. However, in contrast to the 9 overexpresser, SK2 overexpressers do not show enhanced resistance to acoustic injury. Results are consistent with the view that protective effects of MOC activation are mediated via downstream actions of Ca2+ entry other than activation of SK2 channels.
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METHODS |
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SK2 overexpresser mice were created as described in Hammond et al. (2006). Overexpresser mice were created by inserting the tetracycline regulatory cassette 5' of the initiator methionine codon such that the native SK2 promoter drives expression of the tetracycline transactivator (tTA) protein, which in turn induces the transcription of the SK2 gene by binding to the minimal cytomegalovirus (CMVmin) promoter. Male heterozygous SK2 overexpresser mice, maintained as a congenic C57BL/6 strain, were genotyped by PCR for the presence of the tetracycline promotor: TET F: CAGCGCATTAGAGCTGCT and TET off R3: AATGCCCCACAGCGCTGAG. The homozygous SK2 overexpresser is embryonic lethal (Hammond et al. 2006), thus wild-type and heterozygous littermates were compared in the present study. All animals procedures were approved by the IACUC of the Massachusetts Eye and Ear Infirmary.
ABR and DPOAE measurements
Auditory brain stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were measured in each animal at 7 log-spaced frequencies (half octave steps from 5.6 to 45.2 kHz) before and after acoustic overexposure. Mice at age 8–10 wks were anesthetized with xylazine (20 mg/kg ip) and ketamine (100 mg/kg ip). Needle electrodes were inserted at vertex and pinna, with a ground near the tail. ABRs were evoked with 5-ms tone pips (0.5-ms rise-fall with a cos2 onset envelope delivered at 35/s). The response was amplified, filtered and averaged in a LabVIEW-driven data-acquisition system. Sound level was raised in 5 dB steps from 
10 dB below threshold 
80 dB SPL (mean data suggest the start level –if threshold is overestimated, the run is aborted and re-started at a lower SPL). At each sound level, 1024 responses were averaged (with stimulus polarity alternated), using an "artifact reject," whereby response waveforms were discarded when peak-to-peak amplitude exceeded 15 µV. On visual inspection of stacked waveforms, "ABR threshold" was defined as the lowest SPL level at which any wave could be detected, usually corresponding to the level step just below that at which the peak-to-peak response amplitude rose significantly above the noise floor (approximately 0.25 µV). For amplitude versus level functions, the wave I peak was identified by visual inspection at each sound level and the peak-to-peak amplitude computed. DPOAEs at 2f1-f2 were recorded in response to primary tones: f1 and f2 with f2/f1 = 1.2 and f2 level at 10 dB < f1 level. Ear-canal sound pressure was amplified and digitally sampled at 4 µs intervals. Fast Fourier Transform were computed and averaged over 5 consecutive waveform traces, and 2f1-f2 DPOAE amplitude and surrounding noise floor (-10 to –20 dB SPL depending on frequency) were extracted. Iso-response contours were interpolated from plots of amplitude versus sound level, performed in 5 dB steps of f1 level. "DPOAE threshold" is defined as the f1 level required to produce a DPOAE at 0 dB SPL.
Medial olivocochlear assay
A craniotomy and cerebellar aspiration exposed the floor of the IVth ventricle. Shocks were applied through a pair of silver wires placed at the brain stem midline, at an appropriate rostro-caudal location based on surface landmarks. Shock threshold for facial twitches was determined, then paralysis was induced with -D-tubocurarine (1.25 mg/kg ip), and the animal was connected to a respirator. Shock levels were raised 6 dB above twitch threshold. During the MOC suppression assay, f2 level was set to produce a DPOAE approximately 10–15 dB > noise floor. The primary tones were presented continuously, and DPOAE amplitudes were measured roughly every 5 s, before, during and after a 70-s period during which a shock train (150 µs monophasic pulses at 300/s) was delivered to the brain stem electrodes. Magnitude of MOC-mediated suppression was defined as the difference in dB between the mean preshock DPOAE amplitude and the mean of the amplitudes obtained during the first 3 during-shocks measures.
Acoustic overexposure
Animals were exposed free-field, awake and unrestrained, in a small reverberant chamber. Acoustic trauma consisted of a 2-h exposure to an 8–16 kHz octave band noise presented at 100 dB SPL. The exposure stimulus was generated by a custom white-noise source, filtered (Brickwall Filter with a 60 dB/octave slope), amplified (Crown power amplifier), and delivered (JBL compression driver) through an exponential horn fitted securely to a hole in the top of a reverberant box. Sound exposure levels were measured at 4 positions within each cage using a 0.25'' Bruel and Kjaer condenser microphone: sound pressure was found to vary by <0.5 dB across these measurement positions.
Histological analysis
Cochlear morphology was assessed in 4–8 wk old mice via serial sections of either osmium-stained plastic sections or hemotoxylin/eosin-stained paraffin sections. Tissue was fixed by intracardial perfusion with 0.01 M phosphate-buffered saline (PBS) followed by either 4% paraformaldehyde (paraffin sections) or 2.5% glutaraldehyde with 1.25% paraformaldehyde (plastic sections). For both procedures, cochleas were postfixed at 4°C overnight, then decalcified in 120 mM EDTA for 3–7 days, depending on the age. Ears to be plastic-embedded were then osmicated for 1 h in 1% OsO4. All ears were then dehydrated in ethanols, embedded and sectioned at either 12 or 40 µm (in paraffin or plastic, respectively). For paraffin sections, deparaffinized slides were exposed to hematoxylin (ThermoShandon), acid ethanol, ammonium water and eosin (ThermoShandon) before dehydration and coverslipping.
Cochlear immunohistochemistry
After intracardial perfusion buffered 4% paraformaldehyde, cochleas were decalcified as described above and dissected into 6 or 7 segments for subsequent immunostaining. Tissue was permeabilized with TBS containing Triton X-100 overnight, then blocked in TBS containing 1% BSA, 3% normal horse serum for 30 min at room temperature. Tissue was then incubated in TBS containing one or more of the following primary antibodies: mouse anti-synaptophysin (1:2500, Chemicon), rabbit anti-neurofilament-200 (1:1000, Sigma), or vesicular acetylcholine transporter (1:2000; Chemicon), followed by fluorescent-conjugated secondary antibody (1:200, species appropriate, Alexafluor 488 or 594, Molecular Probes, Eugene, OR). Tissue was slide-mounted in gelvatol or vectastain, coverslipped and examined with high-NA immersion objectives in a laser confocal microscope.
RT-PCR
Gene specific primers and probes were designed using Primer Express (see Table 1). RNA isolation was performed using the Versagene tissue kit as described by manufacturer. Cochleae from adult mice (age 3–6 wk), harvested immediately after anesthesia and stored at –70°C, were placed in lysis buffer containing Tris (2-carboxyethyl) phosphine (TCEP). Cochleae were homogenized and lysates were passaged through two columns and washed until RNA was isolated. Individual RNA samples (
2 µg) were then reverse transcribed to generate cDNA using the cDNA High Fidelity Archive kit (Applied Biosystems). Quantitative RT-PCR was performed using a 7900HT Applied Biosystems machine. Experiments were performed in triplicate for each sample including a standard curve. At least two mice per genotype were used. The mRNA in each sample was normalized to murine-specific GAPDH (Applied Biosystems).
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RESULTS |
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). SK2 is the only member of this family highly expressed in the cochlea, where it appears at the basal pole of OHCs, opposite the cholinergic synapses of MOC fibers (Dulon et al. 1998; Oliver et al. 2000). Although SK2 overexpression in this mutant line did not result in the up-regulation of other SK channels in the brain (Hammond et al. 2006); we confirmed in the cochlea, by quantitative RT-PCR, that the eightfold up-regulation of SK2 was not accompanied by changes in either SK1 or SK3 (Fig. 1). Additional RT-PCR results also suggest little change in the expression of nAChR 9 and 10 subunits (Fig. 1), which co-localize with SK2 at the efferent synapses on OHCs.
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; Zheng et al. 1999).
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). To assess whether overexpression of the SK2 channel, and the associated magnification of shock-evoked efferent suppression, leads to enhanced resistance to acoustic injury we exposed matched groups of transgenic overexpressers and wild-type littermates to a noise band designed to produce roughly 30 dB of permanent threshold shifts, as measured 1-wk postexposure. The noise vulnerability of the two genotypes was virtually identical (Fig. 6), whether measured by ABR or DPOAE metrics: group differences were not significant by two-way ANOVA (ABR: F(1,12) = 0.085, P > 0.05; DPOAE: F(1,20) = 0.689, P > 0.05).
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DISCUSSION |
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The binding of ACh to its cochlear receptors sets in motion a complex set of events within the OHCs, which are visible in vivo as suppression of cochlear responses on both fast (tens of ms) and slow (tens of s) time scales (Sridhar et al. 1997; Sridhar et al. 1995). In vitro work suggests that the cholinergic synapses on hair cells couple ACh-gated Ca2+ entry through 9/10 nAChRs to a Ca2+-activated K+ channel, namely the SK2 (Elgoyhen et al. 1994; Elgoyhen et al. 2001; Fuchs and Murrow 1992; Oliver et al. 2000). As described below, the in vivo fast effect is probably associated with SK2 activation, whereas the slow effects are associated with other downstream effects of Ca2+ entry into the OHC.
In vivo, this fast-onset suppression ( 100 ms) can be measured in the sound-evoked vibration amplitudes of the cochlear duct (Cooper and Guinan 2003), as well as all other "downstream" measures of the cochlear transduction cascade from hair-cell receptor potentials (Brown and Nuttall 1984) to sound-evoked discharge rates in single auditory-nerve fibers (Wiederhold and Kiang 1970). In the present experiment, fast suppression is seen as the precipitous drop in DPOAE amplitude visible in the first during-shocks point of the MOC effect assay (Fig. 5A). This "classic" fast effect is 1) potently blocked by strychnine (Kujawa et al. 1994), 2) completely abolished by targeted deletion of the 9 nAChR (Vetter et al. 1999), the 10 nAChR (Vetter et al. 2005a) or the SK2 channel (Vetter et al. 2005b), and 3) enhanced by overexpression of the 9 subunit (Maison et al. 2002) or the SK2 channel (present results). These data are consistent with immunohistochemical and in situ hybridization studies suggesting that 9 (Elgoyhen et al. 1994), 10 (Elgoyhen et al. 2001) and SK2 (Oliver et al. 2000) are all expressed by OHCs, and are also consistent with the known channel properties and pharmacology of 9 and/or 10 receptors expressed in vitro (Elgoyhen et al. 1994; Elgoyhen et al. 2001).
Slower suppressive effects ( 10 s) are also evoked, in vivo, by efferent-mediated ACh release (Sridhar et al. 1995). These slow suppressive effects are harder to study in mouse, because they are often masked by a slow efferent-mediated enhancement of response, which, as we have recently shown, is independent of the OHC nAChRs (Maison and Liberman 2006). In guinea pigs, both slow and fast suppressive effects are blocked by the same palette of cholinergic antagonists, suggesting that both require initial Ca2+ entry through 9/10 nAChRs (Sridhar et al. 1995); and both effects are eliminated by targeted deletion of 9 subunits in mouse (Vetter et al. 1999). However, slow suppression can be selectively enhanced by antagonists of pumps mediating Ca2+ re-uptake into intracellular stores (e.g., thapsigargin and cyclopiazonic acid), suggesting the involvement of a wave of Ca2+-induced Ca2+ release propagated along the subsurface cisternae within the OHCs, both opposite the efferent terminals as well as along much of the cell's basolateral membrane (Sridhar et al. 1997).
In nonmammalian vertebrates, efferent activation in vivo hyperpolarizes the target hair cell and reduces receptor potentials on a time scale consistent with fast effects (Art et al. 1984). Intracellular recordings from mammalian OHCs in vivo during efferent stimulation have not been reported. However, if OHC hyperpolarization and receptor-potential reduction also occur, this would decrease OHC electromotility (Santos-Sacchi et al. 1998) and could account for the reduction in basilar membrane motion and all the other consequent reductions in cochlear sound-evoked responses.
ACh application to isolated OHCs increases electromotility in the load-free condition as it decreases the axial stiffness of the OHCs (Dallos et al. 1997). The effect is blocked by strychnine at concentrations similar to those blocking Ca2+ entry into 9/10 heteromers in vitro (Elgoyhen et al. 2001), consistent with the idea that it is mediated by the cochlea's unique nAChRs. Other evidence suggests that this (slow) cholinergic effect on OHCs in vitro involves Ca2+-mediated phosphorylation of the OHC motor molecular prestin and/or Ca2+-mediated changes in OHC cytoskeletal elements (Sziklai et al. 2001; Zhang et al. 2003). Other in vitro manipulations, such as diamide application, reduce OHC stiffness by interfering with actin cross-linking, and also reduce OHC force generation.
Slow effects observed in vivo in the efferent-mediated suppression of basilar membrane motion are associated with phase lags that are consistent with changes in OHC stiffness (Cooper and Guinan 2003). The relations between in vitro electromotility and in vivo amplification of cochlear motion are complex and poorly understood: nonetheless in some micromechanical cochlear models, a decrease in OHC stiffness reduces basilar membrane vibration at best frequency (Allen 1990).
Fast versus slow effects and the protective actions of the efferent pathway
The efferent pathway to the OHCs constitutes the effector arm of a sound-evoked negative feedback loop, which acts to control the masking of transient stimuli by continuous noise backgrounds and also reduces the ear's vulnerability to acoustic injury (Guinan 1996b). In anesthetized animals, electrical stimulation of the efferent bundle reduces the temporary threshold shifts seen after short-duration high-intensity stimulation (Rajan 1988). In awake animals, the strength of the sound-evoked efferent reflex is a strong predictor of vulnerability to permanent acoustic injury (Maison and Liberman 2000), and unilateral surgical section of the efferent bundle significantly increases noise-induced permanent threshold shifts seen in the de-efferented ear (Kujawa and Liberman 1997).
Circumstantial evidence, based largely on the frequency dependence of the effects, has suggested that efferent-mediated protection is associated with slow rather than fast effects of cholinergic transmission (Reiter and Liberman 1995). Results of the present study provide additional evidence, of a more direct nature, for that hypothesis. A previous study (Maison et al. 2002) showed that transgenic overexpression of 9 nAChRs (1.7-fold increase by Western blot in homozygotes) increased fast effect magnitude by at most approximately 4 dB (measured at 22 kHz) and decreased permanent noise-induced threshold shift from about 40 dB (in wild types) to about 20 dB (in homozygotes). In the present study, SK2 overexpression (almost eightfold by qRT-PCR: Fig. 1) produced a significant enhancement of efferent-mediated fast effects (by as much as approximately 7 dB at 22 kHz: Fig. 5), yet caused no change in noise vulnerability (Fig. 6). The noise exposure band (8–16 kHz), and thus the cochlear regions maximally affected by the trauma (20 kHz), were identical in the two studies; thus the pre-exposure threshold elevations at frequencies >32 kHz in the present study are not a significant complication. However, hints that protective effects of cochlear manipulations such as heat shock differ between the extreme base and the rest of the cochlea (Yoshida et al. 1999) suggest that re-evaluation of both SK2 and 9 overexpression in a mouse model with better function at very high frequencies could be informative.
These results are consistent with the notion that the protective effects of efferent cholinergic transmission arise from downstream effects of Ca2+ entry other than those involving SK2 activation and the subsequent increase of K+ conductance, cell hyperpolarization and the decrease in receptor potential and OHC electromotility that follow from it. It is interesting, in this regard, that the Ca2+ permeability of the 9/10 receptor complex is particularly large, compared with other nAChRs (Weisstaub et al. 2002). Downstream effects of Ca2+ entry could include protein phosphorylation, or other structural modifications, that decrease the sound-evoked mechanical motions of the partition. Although efferent suppressive effects tend to be largest at low sound pressure levels, even at high sound levels, efferent activity can decrease vibrations in a manner equivalent to a decrease in input of a few dB (Russell and Murugasu 1997), and relatively small changes in effective sound level can have large effects on noise damage (Yoshida et al. 2000). It is also possible that the protective effects of cholinergic signaling at the cochlear hair cell involve changes in expression of anti-apoptotic pathways, as has been proposed as a downstream effect of nAChR signaling via 7 and other subunits in studies of neural degeneration in vivo and in vitro (for review see Dajas-Bailador and Wonnacott 2004).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S. F. Maison, Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02114-3096 (E-mail: sfm{at}epl.meei.harvard.edu)
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REFERENCES |
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