Overexpression of SK2 Channels Enhances Efferent Suppression of Cochlear Responses Without Enhancing Noise Resistance

Abstract

Cochlear hair cells express SK2, a small-conductance Ca(2+)-activated K(+) channel thought to act in concert with Ca(2+)-permeable nicotinic acetylcholine receptors (nAChRs) alpha9 and alpha10 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 alpha9/alpha10 nAChRs. Shock-evoked efferent suppression of cochlear responses was significantly enhanced in overexpresser mice as seen previously in alpha9 overexpresser mice; however, in contrast to alpha9 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 Ca(2+) entry different from those involving SK2-mediated hyperpolarization and the associated reduction in outer hair cell electromotility.

Presynaptic maturation in auditory hair cells requires a critical period of sensory-independent spiking activity

“…We would predict that in SK2 OE mice, the higher IHC exocytosis Ca 2+ dependence would lead to a narrowing of their dynamic range, causing a reduced sensitivity to low intensity sounds and possibly an overstimulation to those of high intensity. However, we found that auditory brainstem responses (ABRs) in SK2 OE mice, which reflect the activity of the auditory nerve, were normal in agreement with previous observations (31). It is possible that ABRs are not sensitive enough to resolve the reduced exocytotic Ca 2+ dependence, or alternatively, some compensatory mechanism within the auditory pathway may have occurred during the development of OE mice (14).…”

Contextual memory deficits observed in mice overexpressing small conductance Ca2+-activated K+ type 2 (KCa2.2, SK2) channels are caused by an encoding deficit

“…However, SK2+/T mice froze significantly less in response to the tone (min 2) than did the WT mice, t 24 = 2.39; P < 0.03 consistent with our previous report (Hammond et al 2006). In light of the recent demonstration that auditory stimuli in the range used in the present study produced auditory brainstem responses in SK2+/T mice that were not different from those of WT mice (Maison et al 2007), we conclude that the deficits of the SK2+/T mice in cued fear conditioning are not due to sensory impairments.…”

Ca2+-Activated K+Channels: From Protein Complexes to Function

“…Stimulation of CK2 activity induces and maintains rapid IPSC deactivation kinetics, indicating that the machinery for modulation of the Ca2+ sensitivity is present in these cells. At present, this regulatory mecha nism is implied in suppression of Ca2+ APs in immature IHCs prior to the onset of hearing (67), and in hyperpo larization shunting of OHCs to limit the amplitude of the receptor potential and the active cochlear amplification during periods of high sound-pressure levels (125,138).…”