Protection from Noise-Induced Hearing Loss by Kv2.2 Potassium Currents in the Central Medial Olivocochlear System

Abstract

The central auditory brainstem provides an efferent projection known as the medial olivocochlear (MOC) system, which regulates the cochlear amplifier and mediates protection on exposure to loud sound. It arises from neurons of the ventral nucleus of the trapezoid body (VNTB), so control of neuronal excitability in this pathway has profound effects on hearing. The VNTB and the medial nucleus of the trapezoid body are the only sites of expression for the Kv2.2 voltage-gated potassium channel in the auditory brainstem, consistent with a specialized function of these channels. In the absence of unambiguous antagonists, we used recombinant and transgenic methods to examine how Kv2.2 contributes to MOC efferent function. Viral gene transfer of dominant-negative Kv2.2 in wild-type mice suppressed outward K ϩ currents, increasing action potential (AP) half-width and reducing repetitive firing. Similarly, VNTB neurons from Kv2.2 knock-out mice (Kv2.2KO) also showed increased AP duration. Control experiments established that Kv2.2 was not expressed in the cochlea, so any changes in auditory function in the Kv2.2KO mouse must be of central origin. Further, in vivo recordings of auditory brainstem responses revealed that these Kv2.2KO mice were more susceptible to noise-induced hearing loss. We conclude that Kv2.2 regulates neuronal excitability in these brainstem nuclei by maintaining short APs and enhancing high-frequency firing. This safeguards efferent MOC firing during high-intensity sounds and is crucial in the mediation of protection after auditory overexposure.

Kv2 Channel Regulation of Action Potential Repolarization and Firing Patterns in Superior Cervical Ganglion Neurons and Hippocampal CA1 Pyramidal Neurons

“…Our results using GxTX-1E block adds to previous results using knock-out, antisense, and dominant-negative strategies to suggest an importance of Kv2 channels for enabling repetitive firing that extends over a wide range of neuronal types (Du et al, 2000;Malin and Nerbonne, 2002;Guan et al, 2013;Tong et al, 2013). Our data also fit well with previous proposals (Johnston et al, 2010;Guan et al, 2013;Tong et al, 2013) that the key factor of Kv2 activation to enable repetitive firing is to promote strong afterhyperpolarization as a consequence of slow deactivation. We find that this effect of Kv2 activation is prominent even after the first action potential in a train and is maintained during firing over half a second.…”

“…Even though only a small fraction of Kv2 channels are likely to be activated at the time of half-repolarization, the very large amplitude of maximal Kv2 current means this partial activation can be significant. An even more striking example of the importance of Kv2 channels for spike repolarization was reported for auditory neurons in the ventral and medial nuclei of the trapezoid body, in which loss of Kv2.2 channels resulted in substantial spike broadening even for much narrower (0.3-0.5 ms) spikes (Tong et al, 2013).…”

“…Kv2 channels are subject to a remarkable range of modulatory influences that can alter functional expression (Misonou et al, 2004;O'Connell et al, 2010;Fox et al, 2013) through regulation by phosporylation (Murakoshi et al, 1997;Mohapatra et al, 2007;Cerda and Trimmer, 2011;Ikematsu et al, 2011), sumoylation (Plant et al, 2011, and nitric oxide-associated pathways (Steinert et al, 2011). This modulation can mediate plasticity of neuronal firing (Mohapatra et al, 2009;Nataraj et al, 2010;Steinert et al, 2011), although, in general, it is difficult to be certain that changes in firing from modulatory influences are exclusively due to changes in Kv2.…”

“…In both CA1 and sympathetic neurons, loss of Kv2 disrupts maintained repetitive or tonic firing (Du et al, 2000;Malin and Nerbonne, 2002;Guan et al, 2013), an effect seen also with computer modeling of neuron firing in the medial nucleus of the trapezoid body (Johnston et al, , 2010. The function of Kv2 channels is of particular interest because of highly plastic expression (Misonou et al, 2005;Nataraj et al, 2010;Fox et al, 2013) and strong modulation by multiple pathways (Mohapatra et al, 2007;Cerda and Trimmer, 2011;Plant et al, 2011;Steinert et al, 2011).…”

Physiology and anatomy of neurons in the medial superior olive of the mouse

“…Mouse MSO neurons respond to sustained depolarizing current injections with a single, onset action potential, consistent with reported responses from gerbil and guinea pig (Baumann et al 2013; Couchman et al 2010; Scott et al 2005; Smith 1995). SPN and VNTB neurons typically fire trains of large-amplitude action potentials in response to current injections at amplitudes only slightly above threshold (SPN: Felix et al 2013; Kopp-Scheinpflug et al 2015; Yassin et al 2014; VNTB: Tong et al 2013). SPN neurons can be distinguished by firing rebound bursts after hyperpolarizing current injection, a phenomenon rarely observed in MSO neurons (Felix et al 2011, 2013; Kopp-Scheinpflug et al 2011, 2015; Yassin et al 2014).…”