Extraction of Auditory Information by Modulation of Neuronal Ion Channels
Abstract and Keywords
All neurons express a subset of over seventy genes encoding potassium channel subunits. These channels have been studied in auditory neurons, particularly in the medial nucleus of the trapezoid body. The amplitude and kinetics of various channels in these neurons can be modified by the auditory environment. It has been suggested that such modulation is an adaptation of neuronal firing patterns to specific patterns of auditory inputs. Alternatively, such modulation may allow a group of neurons, all expressing the same set of channels, to represent a variety of responses to the same pattern of incoming stimuli. Such diversity would ensure that a small number of genetically identical neurons could capture and encode many aspects of complex sound, including rapid changes in timing and amplitude. This review covers the modulation of ion channels in the medial nucleus of the trapezoid body and how it may maximize the extraction of auditory information.
It has been known since the 1970s that the excitability of neurons is not fixed. Fundamental characteristics of a neuron, such as the height and width of its action potentials, firing rate and the absence or presence of adaptation to a maintained synaptic barrage, can be altered in response to synaptic or hormonal stimulation. Most commonly such changes are brought about by posttranslational modifications such as phosphorylation of ion channels in the plasma membrane, or by the acute insertion or removal of channels from the membrane. In many cases, particularly in well-studied invertebrate models, the biological significance of such modulation is apparent. For example, changes in potassium and calcium currents that alter transmitter release at sensory neurons underlie behavioral phenomena such as habituation and sensitization (Kandel & Schwartz, 1982). In other neurons, similar stimulation-induced changes in potassium, calcium and non-selective cation channels trigger a prolonged period of spontaneous firing that causes a series of reproductive behaviors lasting many hours (Conn & Kaczmarek, 1989).
The need for such modulation of ion channels in neurons of the central auditory system is, at first glance, less apparent. Many auditory neurons, particularly in brainstem nuclei, fire at rates of up to many hundreds of Hz and lock their action potentials to auditory events with microsecond precision (Joris, 1996; Joris & Yin, 1995; Kopp-Scheinpflug, Tolnai, Malmierca, & Rubsamen, 2008). Such high rates and temporal precision are required for the transmission of auditory information and for the detection of small differences in pitch and location of sounds. One might imagine that accurate detection of such nuances in sensory information would be best achieved by having neurons that are invariant in their response properties, and that modulation of ion channels over time could alter firing patterns and introduce errors that degrade the signal. It is known, however, that that many of the ion channels in auditory brainstem nuclei are regulated by second messenger pathways and that rapid changes in phosphorylation state, current amplitude, and rates of channel synthesis and transcription are produced by auditory stimulation.
This review will describe the modulation of several types of ion channels in auditory brainstem nuclei, particularly in the medial nucleus of the trapezoid body (MNTB), a nucleus that participates in circuits for the localization of sounds in space, and in which there have been many studies of channel modulation. Rather than focus on the mechanisms by which modulation occurs, which have been described in other reviews (Gan & Kaczmarek, 1998; Johnston, Forsythe, & Kopp-Scheinpflug, 2010; Kaczmarek, 2017; Kaczmarek et al., 2005; Schneggenburger & Forsythe, 2006; Taschenberger & von Gersdorff, 2000), the emphasis will be on the potential biological implication of such modulation and on the potential benefits for auditory processing of allowing individual neurons to take on a variety of electrophysiological personalities.
The MNTB and Binaural Processing
Figure 1 shows a schematic diagram of auditory brainstem circuits that underlie the detection of interaural differences in timing and levels of incoming sounds. Bushy cells in anterior cochlear nucleus receive inputs from the ipsilateral cochlea. Information from these cells is communicated to the medial and lateral olivary nuclei (MSO and LSO) where inputs from the two ears are compared directly. An intermediate nucleus in this network is the MNTB. The glycinergic neurons in this nucleus receive strong excitatory input from the bushy cells and relay this in the form of inhibition to both the MSO and LSO. These inhibitory inputs are required for the determination of differences in both the level and timing of sounds received by the two ears (Grothe, 2003).
The synaptic drive from the bushy cells to the principal neurons of the MNTB is provided by the very large calyx of Held presynaptic terminals (Schneggenburger & Forsythe, 2006). These provide very secure and very precisely timed excitation at the somata of the MNTB neurons, allowing MNTB neurons to lock their action potentials to the phase of sound stimuli of frequencies up to 2000 Hz or more, and also to the envelope of higher-frequency sounds that are amplitude-modulated at frequencies up to ~2000 Hz (Joris, 1996; Joris & Yin, 1995). The firing rate of MNTB neurons, however, is dependent on the amplitude, as well as the frequency, of incoming sounds. Even in silence, MNTB neurons are driven to fire at rates from 10 to >200 Hz by the level of spontaneous transmitter release from hair cells that occurs even in the absence of auditory stimulation (Kopp-Scheinpflug et al., 2008). As the amplitude of sounds is increased, the firing rate of MNTB neurons can be pushed to over 800 Hz. Thus these neurons respond to changes in the timing and amplitude of auditory stimuli.
Potassium Channels Operate in Different Voltage Ranges
While the excitability of all neurons is determined by several types of ion channels, including those selective for sodium, calcium and chloride, as well as by non-selective cation channels, the greatest diversity is provided by potassium channels. There are over seventy different genes that encode subunits of K+ channels, and many of these can combine to form heteromeric channels. This, coupled with the existence of different channel isoforms produced alternative splicing, provides an immeasurable number of potential different K+ channels. Figure 2B lists the potassium channel subunits that are currently known and categorizes them by the mechanism for their activation. Also indicated are the subset of potassium channels that have been localized in the MNTB. These are marked in bold and color. The general properties of these channels will be described in a later section.
One way that K+ channels differ from each other is in the range of voltages in which they operate (Figure 2A). Some K+ channels are already open near the resting potential of a neuron (~–65 mV for an MNTB neuron). These include leak channels that are open at all voltages, and so-called low-threshold or low-voltage activated channels that are open close to the resting potential and that increase their open probability with small depolarizations from rest (Figure 2A). In contrast, high-threshold voltage-dependent K+ channels typically open only when the membrane potential becomes more positive than about –15 mV. Under physiological conditions, such positive membrane potentials are only encountered during an action potential, and the primary role of these channels is to provide rapid repolarization of action potentials. Although, strictly speaking, the activation of a channel has no fixed threshold, the terms low threshold and high threshold are useful in that they refer to potentials at which measurable currents can first be detected in voltage clamp experiments.
Altering Potassium Channels Alters the Type of Information Extracted from Synaptic Inputs
Before describing the types of channels in MNTB neurons in more detail, we will discuss how differences in the voltage-dependence of K+ currents influence firing patterns using a simple computational model. Figure 3 shows the response of model neurons to trains of synaptic inputs. The voltage-dependent K+ current in the model in Figure 3A is a high-threshold current that provides very rapid repolarization of action potentials. As the amplitude of the synaptic currents applied to these neurons is increased, the rate of firing of the neurons increases. The timing of most of the action potentials during the synaptic depolarization is independent of the precise timing of the synaptic inputs. As a result, such a neuron provides a code in which the firing rate of the neurons encodes the amplitude of the synaptic stimulus train.
In Figure 3B, the total level of potassium conductance in the model neuron is the same as that in Figure 3A, and the other parameters are identical. The voltage-dependence of the potassium current has, however, been altered so that it now activates at more negative potentials, close to the resting membrane potential. This has the effect of decreasing the membrane time constant and increasing the threshold for triggering an action potential. A train of synaptic stimuli similar to that in Figure 3A now evokes a very different response. Once the threshold for triggering an action potential is reached, each synaptic potential within the train triggers only a single action potential, and this is now independent of the amplitude of the stimulus (Figure 3B). Such a neuron therefore encodes only the timing, but not the amplitude of the synaptic stimulus.
Firing patterns such as those in Figure 3 have been extensively characterized in auditory brainstem nuclei. For example, stellate cells of the ventral cochlear nucleus have firing patterns similar to those of Figure 3A, and these are sometimes termed chopper patterns (Oertel, Wright, Cao, Ferragamo, & Bal, 2011), while bushy cells in the anteroventral cochlear nucleus, as well as the principal neurons of the MNTB phase-lock their action potentials to sound stimuli and have firing pattern that more closely resemble those of Figure 3B (Manis & Marx, 1991; Trussell, 1999).
In contrast to the simple model of Figure 3, all neurons express the genes for more than one type of potassium channel. The vast majority of neurons, including those that primarily encode amplitude or timing information, have multiple components of potassium currents that activate at both positive and negative potentials. The ratios of such components, however, differ in the different cell types such that each neuron in an auditory nucleus expresses a slightly different blend of channels. The most common distribution, and one that is found for many of the channels in Figure 2B, is a tonotopic gradient along the tonotopic axis. As one example, the high-threshold Kv3.1 potassium channel is expressed at highest levels at the medial, high frequency aspect of the MNTB and other auditory nuclei (Brew & Forsythe, 2005; Li, Kaczmarek, & Perney, 2001; Figure 4). In contrast, as will be described later, some channels are expressed in a gradient in the opposite direction, with highest levels in the lateral, low-frequency part of the MNTB. Note from Figure 4 that, although the existence of the tonotopic gradient is obvious, it is not a smooth gradient, and that some cells with low levels of Kv3.1 can be found at the medial end, while a few neurons in the lateral region also appear to have a high level of Kv3.1.
How Does Diversity of Ion Channel Expression Arise?
How do gradients, in which neighboring neurons express slightly different levels of potassium channels from their immediate neighbors, come about? The topographic organization of axons and synaptic connections from the cochlea through to all auditory brainstem nuclei is already present very early in development. At least in part, this may arise from the action of growth factors and other morphogens such as ephrins, which that may be secreted preferentially from cells beyond the medial or lateral aspects of the nucleus (Cramer, 2005; Cramer & Miko, 2016). The connections are then refined before the onset of hearing by patterns of spontaneous activity that are generated in cochlear hair cells and then propagated to brainstem nuclei (Clause et al., 2014; Kandler, Clause, & Noh, 2009).
At least some of the same factors that contribute to the topographic pattern of connectivity may also influence the levels of potassium channels in brainstem neurons. Nevertheless, the existence of gradients in potassium channels depends on ongoing neuronal activity, even in adults. For example, strains of mice that have normal hearing throughout their lifespan maintain normal tonotopic gradients of Kv3.1, whereas those that undergo hearing loss with age progressively lose this gradient (Figure 4; von Hehn, Bhattacharjee, & Kaczmarek, 2004). Gradients of channel expression and activity are absent in congenitally deaf mice (Leao et al., 2006).
It is well established that gradients, as well as more complex spatiotemporal patterns, can be generated in an ensemble of originally identical cells, provided the individual cells interact with their neighbors to influence the synthesis of components in nearby cells (Nicolis & Prigogine, 1977). A change in the level of a component in one unit, brought about by a transient external stimulus, results in the self-organization of the entire group of cells into a gradient or other spatiotemporal pattern. The hypothesis advanced in this article is that such interactions between nearby neurons in auditory nuclei such as the MNTB result in the establishment of tonotopic gradients in potassium channels and other components. Specifically, an elevation in levels of one type of potassium channel subunit in a neuron produces a decrease in expression of the same subunit in neighboring neurons. This alone could be responsible for establishing a gradient.
The consequences of such “lateral inhibition” of channel expression go beyond simply establishing a gradient. They may enhance the amount of information propagated through the nucleus. Take the simple hypothetical example of two identical neurons both of which are exposed to the same complex stimulus pattern (Figure 5). If the potassium conductance of these neurons is dominated by high-threshold currents, such as those of Kv3 family channels, the action potentials will reflect primarily changes in stimulus amplitude (Figure 5A). Conversely, if the potassium conductance of these neurons is dominated by low-threshold currents, such as those of Kv1 family channels, the neurons will fire with action potentials that are phase-locked to the onset of transients in the stimulus (Figure 5B). In this case, the output of the neurons will contain little information about changes in signal amplitude during the stimulus. If, however, the two neurons interact laterally, a stimulation-induced increase in high-threshold current in one neurons could trigger a decrease in the same current in its neighbor. Assuming there exist mechanisms to maintain total levels of potassium current constant, these interactions will result in a two-neuron “gradient” with one neuron faithfully tracking timing information and the second monitoring stimulus amplitude (Figure 5C). This will, of course, greatly increase the amount of information being transmitted over what is possible with identical neurons.
Diversity of K+ Conductance Enhances Throughput of Information in a Network
The hypothetical model in Figure 5 is clearly an extreme example, and it is perhaps unlikely that two neighboring neurons would come to encode such different aspect of a stimulus. Whatever the mechanism for generating diversity, however, even small differences in the intrinsic excitability of different neurons in a network can dramatically enhance the ability of that network to extract the maximal information about the amplitude and timing of its synaptic inputs. This can readily be demonstrated in numerical computations of MNTB-like neurons. Figure 6 shows the response of each neuron in an ensemble of 50 neurons to stimulation at 700 Hz (Kaczmarek, 2012). The firing pattern of each neuron is shown as a raster plot under the stimuli. The neuronal units in this ensemble are unable to follow 700 Hz but respond to the stimulus with a lower rate of firing. Also shown in the figure is a color-coded adjusted phase vector strength, which is calculated by determining the accuracy with which individual units are locked in time to the stimuli, as well as the degree of entrainment to the stimulus train (Kaczmarek, 2012). This is calculated for individual units (convergence of units =1) as well as the output of the entire network (convergence of inputs = 50). When all units are identical, there is no additional information in the output of the ensemble over that in a single cell, and the adjusted phase vector strength is the same for single neurons and the entire network (Figure 6, top). Introducing diversity in the levels of a high-threshold K+ current substantially increases the information encoded in the output of the ensemble over that in individual neurons (Figure 6, center). Counterintuitively, introducing even more diversity by simply allowing spontaneous random firing of the input results in an even further increase in overall accuracy of the output of the ensemble (Figure 6, bottom). This is because the spontaneous activity alters the intrinsic excitability of different units at the time of arrival of phase-locked information in the inputs.
Even though random spontaneous perturbations improve the accuracy of an ensemble, this does not mean that randomizing the expression of levels of ion channel subunits is a useful strategy for optimal accuracy. Computations similar to those in figure 6 have demonstrated that maximal information can be propagated through the ensemble if the levels of conductance in different neurons can specifically be adjusted to the pattern of synaptic inputs (Kaczmarek, 2012). As with the hypothetical case shown in Figure 5, if such adjustments are made in real auditory nuclei such as the MNTB, they are likely to involve lateral interactions between individual neurons.
Types of Potassium Channels in the MNTB
This section will provide more molecular details of the types of potassium channels expressed in MNTB neurons.
Low-Threshold Potassium Channels
The Kv1 subfamily of potassium channel subunits are the prototypical low-threshold channels. At least four members of this group (Kv1.1, Kv1.2, Kv1.3. and Kv1.6) have been found within the MNTB (Brew & Forsythe, 1995; Brew, Hallows, & Tempel, 2003; Dodson, Barker, & Forsythe, 2002; Dodson et al., 2003; Gazula et al., 2010; Grigg, Brew, & Tempel, 2000; Johnston et al., 2010; Kopp-Scheinpflug, Fuchs, Lippe, Tempel, & Rubsamen, 2003). The voltage-dependence of these is such that they open at or near the resting potential of MNTB neurons and are strongly activated by small depolarizations from rest. In principal neurons of the MNTB, this has the effect of limiting firing to a single action potential at the onset of an excitatory synaptic input or of a sustained depolarization. The opening of Kv1 channels near the resting potential also provides neurons with a short membrane time constant. These features provide neurons with the ability to lock their action potentials to incoming stimuli with high temporal accuracy. This role for low-threshold potassium currents was first described in bushy cells of the cochlear nucleus (Manis & Marx, 1991).
The different Kv1 family subunits are localized in different compartments of the MNTB. Kv1.1/Kv1.2 heteromeric channels are localized to the initial segment of the axon of postsynaptic neurons, but are absent from the presynaptic calyx of Held terminal and from the postsynaptic cell bodies of MNTB neurons (Dodson et al., 2002). Kv1.2 homomers as well as Kv1.1/1.2 heteromers exist on presynaptic axons coming from the cochlear nucleus, but are absent from the membrane of the presynaptic terminal itself (Dodson et al., 2003). In contrast Kv1.3 channels are found selectively in the plasma membrane of the presynaptic terminal and on intracellular vesicles within the terminal (Gazula et al., 2010).
Low-threshold K+ currents and Kv1 family channel subunits have been found to be expressed along a tonotopic gradient in the MNTB and in other auditory nuclei in different species (Adamson, Reid, Mo, Bowne-English, & Davis, 2002; Barnes-Davies, Barker, Osmani, & Forsythe, 2004; Brew & Forsythe, 2005; Fukui & Ohmori, 2004; Gazula et al., 2010; Leao et al., 2006; Walmsley, Berntson, Leao, & Fyffe, 2006). In the MNTB, Kv1.1 and Kv1.3 have been found to be expressed at highest levels in lateral low-frequency neurons (Gazula et al., 2010; Leao et al., 2006). As with the Kv3.1b channel, levels of low-threshold K+ currents are reduced and corresponding tonotopic gradients are abolished in deaf animals (Leao, Berntson, Forsythe, & Walmsley, 2004; Leao et al., 2006).
Two other subunits of the voltage-dependent channel family, Kv11.1 and Kv11.3 (ERG1 and ERG3), also contribute to the low-threshold currents that activate near rest in MNTB neurons of mice, but not of rats (Hardman & Forsythe, 2009). In addition, Na+-activated K+ channel subunits, KNa1.1 and KNa1.2 (Slack and Slick), are expressed in MNTB neurons (Bhattacharjee, Gan, & Kaczmarek, 2002; Bhattacharjee, von Hehn, Mei, & Kaczmarek, 2005). Like Kv1 and Kv11 subfamily channels, these channels open near the resting potential, and their activity is further increased by elevations of cytoplasmic Na+ levels (Kaczmarek, 2013; Kaczmarek et al., 2017). Pharmacological activation of these channels increases the temporal accuracy of firing of firing of MNTB neurons in brainstem slices (Yang, Desai, & Kaczmarek, 2007).
Despite our knowledge about the types of low-threshold channels in the MNTB, there is little information about what regulates the levels of these channels. It is also not known if rapid changes in current amplitude are produced by stimulation of synaptic inputs. In particular, the molecular mechanisms that regulate the expression or modulation of Kv1 family channels in MNTB neurons are not yet well understood. As in other neurons, the activity of KNa channels is expected to be increased by Na+ entry during high frequency activity, and these channels are potently regulated by protein kinase C activation (Barcia et al., 2012; Santi et al., 2006). The role of their phosphorylation in MNTB neurons has not yet been investigated.
Leak K+ Channels
A leak conductance is defined as one that has no time dependence and little or no voltage dependence. Technically, therefore, a leak conductance would be open at rest and contribute to setting the resting potential, the time constant and the threshold for action potential generation. Such a leak K+ conductance, which is typically produced by members of the two pore domain K2P channel family, has been characterized in MNTB neurons (Berntson & Walmsley, 2008). Messenger RNA for K2P1.1 (also known as TWIK) is strongly expressed in MNTB neurons (Kaczmarek et al., 2005), and the leak current in these currents is generally consistent with the properties of K2P1.1 currents (Berntson & Walmsley, 2008). As for the low-threshold channels, there have been no studies of mechanisms that determine expression levels of leak channels in the MNTB.
“Intermediate Threshold” Potassium Channels
The Kv2.2 potassium channel is expressed in a tonotopic gradient in the MNTB neuron, with highest levels found at the axon hillock of neurons within the medial, high frequency end of the nucleus (Johnston, Griffin, Baker, Skrzypiec et al., 2008; Tong et al., 2013). Unlike the channels listed in the preceding two sections, Kv2.2 channels are not open at typical resting potentials (~ –65 mV) but begin to activate with depolarizations to ~ –40 mV and are half-activated by ~ –10 mV. Their activation with voltage is relatively slow. As a result, they do not contribute significantly to the onset or shape of a single evoked action potential, but contribute to the hyperpolarization between action potentials during repetitive firing (Johnston, Griffin, Baker, Skrzypiec et al., 2008; Tong et al., 2013). Elimination of Kv2.2 currents reduces the number of action potentials that can be evoked during trains of high frequency stimuli.
Levels of Kv2.2 currents in MNTB neurons do not remain constant over time. Spontaneous neurotransmitter release from cochlear hair cells in vivo drives the synaptic input to MNTB neurons at rates of 10 Hz up to 150 Hz or more even in the absence of auditory stimulation (Brownell, 1975; Kopp-Scheinpflug, Lippe, Dorrscheidt, & Rubsamen, 2003). In MNTB neurons within brain slices, the amplitude of Kv2.2 currents in MNTB neurons is increased by prolonged stimulation of synaptic inputs at such low rates (~10 Hz for 1 hour; Steinert et al., 2011). Such low-frequency stimulation is therefore likely be represent the default situation in quiet environments, suggesting Kv2.2 channels contribute to repolarization in this situation. The increase in Kv2.2 currents is produced by the release of the volume transmitter nitric oxide (NO) during low frequency stimulation (to be discussed further) and the activity of both the cyclic GMP-dependent protein kinase and protein kinase C (Steinert et al., 2011).
High-Threshold Potassium Channels
The Kv3 family of K+ subunits is required for many neurons in the nervous system to fire at high rates (Kaczmarek & Zhang, 2017). This family also regulates the repolarization of action potentials in many presynaptic terminals, controlling the amount of neurotransmitter release during the action potential. The canonical high-threshold K+ channel in the MNTB is Kv3.1b, which is expressed in the soma of the postsynaptic principal MNTB neurons as well as in the calyx of Held presynaptic terminals (Figure 4; Elezgarai et al., 2003; Li et al., 2001; Macica & Kaczmarek, 2001; Song et al., 2005). Under normal conditions, Kv3.1b channels do not begin to activate until the membrane potential reaches about –15 to –10 mV and half-maximal activation occurs at ~ +15 mV (Brown et al., 2016; Luneau et al., 1991). Kv3.3 channels have properties similar to those of Kv3.1 (Kaczmarek & Zhang, 2017), but are localized primarily to the membrane of the presynaptic terminals (Zhang et al., 2016). Elimination of Kv3 currents by pharmacological agents or deletion of the Kv3.1 gene impairs the ability of MNTB neurons to follow stimulation at rates greater than 200 Hz (Macica et al., 2003; Wang, Gan, Forsythe, & Kaczmarek, 1998)
Both the activity and synthesis of Kv3.1b channels are altered in response to changes in the auditory environment. One mechanism that can rapidly alter Kv3.1b currents is changes in its phosphorylation state. In rats, serine residue 503 in the cytoplasmic C-terminus of the channel can be phosphorylated by PKC, which produces a partial suppression of high-threshold current (Kanemasa, Gan, Perney, Wang, & Kaczmarek, 1995; Macica et al., 2003; Song & Kaczmarek, 2006). In vivo, in a quiet environment, the serine 503 site is basally phosphorylated, but physiological increases in sound levels for only five minutes or less activate a phosphatase that rapidly dephosphorylates the channel (Figure 7A; Song et al., 2005). Similar dephosphorylation of Kv3.1b occurs in brain slices of the MNTB in response to stimulation of the presynaptic input at 600 Hz, increasing Kv3.1b current and allowing neurons to maintain firing at high rates of stimulation (Song et al., 2005). Conversely, stimulation at much lower frequencies (10–100 Hz) for up to an hour suppresses Kv3.1 currents, an effect that is mediated by synthesis and release of NO and resultant changes in phosphorylation, although direct links to the serine 503 site have not been established (Steinert et al., 2008; Steinert et al., 2011).
In intact animals, auditory stimulation similar to that which causes dephosphorylation of Kv3.1b, but for a slightly longer time (30 minutes or more), produces increases in levels of Kv3.1b protein in both mice and rats (Figure 7B; Leão et al., 2010; Strumbos, Brown, Kronengold, Polley, & Kaczmarek, 2010; Strumbos, Polley, & Kaczmarek, 2010). This produces a further increase in high-threshold K+ current and increased repolarization of action potentials (Leão et al., 2010). The greatest increases occur in neurons along the tonotopic axis corresponding to the frequency of the auditory stimulus (Figure 7C; Strumbos, Polley et al., 2010). Interestingly, levels of Kv3.1b in neurons in regions of the MNTB not expected to be activated by the sound stimulus appears to decrease (Strumbos, Polley et al., 2010), a finding consistent with some form of lateral inhibition of channel synthesis across the nucleus.
The mechanism which auditory stimulation increases levels of Kv3.1b protein involves the regulation of translation of mRNA by the Fragile X Mental Retardation Protein FMRP, an RNA-binding protein that directly binds Kv3.1b mRNA (Darnell et al., 2001; Strumbos, Brown et al., 2010). In mice lacking FMRP, auditory stimulation fails to produce any increase in level of the channel, and the normal tonotopic gradient of Kv3.1 protein in the MNTB is absent (Strumbos, Brown et al., 2010).
Finally, long-term changes in the production of Kv3.1b channels in the MNTB and other nuclei are regulated by alterations in the rate of transcription of the Kv3.1 gene. As will be described later, the transcription of Kv3.1, and likely of other channels such as Kv3.3, is regulated by the transcription factor CREB (cAMP response element-binding protein; Gan & Kaczmarek, 1998; Gan, Perney, & Kaczmarek, 1996; Tong et al., 2010).
Transient A-Type Potassium Channels
Once activated by depolarization, a subset of voltage-dependent K+ channels rapidly inactivate if the depolarization is maintained. The currents of such channels are termed A-currents (Connor & Stevens, 1971b). In addition to contributing to the repolarization of action potentials, A-currents have two major functions: (1) regulating the rate of repetitive firing and (2) introducing a delay between the time that a neuron receives an excitatory stimulus and the onset on firing (Byrne, 1980; Connor & Stevens, 1971a; Strong & Kaczmarek, 1986). Because timing delays play a key role in the discrimination of interaural timing and level differences (Brand, Behrend, Marquardt, McAlpine, & Grothe, 2002; Grothe, 2003), A-currents could potentially play an important role in the processing of information through the MNTB. Currents corresponding to the Kv4.3 A-type K+ channel subunit, as well as Kv4.3 immunoreactivity have been found in MNTB neurons of mice but not rats (Johnston, Griffin, Baker, & Forsythe, 2008). Numerical simulations suggest that this current may influence the response of the neurons to small excitatory inputs such as those from non-calyceal inputs (Johnston, Griffin, Baker, & Forsythe, 2008), but the precise role of these channels, and whether they undergo regulation in MNTB neurons is not known.
Immunoreactivity for another A-type channel, Kv3.4, is present in the calyx of Held presynaptic terminals (Ishikawa et al., 2003). This high-threshold K+ channel subunit typically inactivates rapidly (within 10–15 msec) at positive potentials, a process that is regulated by PKC phosphorylation of residues in the cytoplasmic N-terminal domain (Beck, Sorensen, Slater, & Covarrubias, 1998; Covarrubias, Wei, Salkoff, & Vyas, 1994). As with Kv4.3, the modulation and physiological significance of Kv3.4 channels in the presynaptic terminals is not yet understood. No gradients in either A-type currents or in Kv3.4 immunoreactivity has been found along the medio-lateral axis of the MNTB (Leao et al., 2006). It is possible that Kv3.4 subunits play a role in development and the establishment of synaptic contacts, because they are expressed abundantly in most fiber tracts and their growth cones during pathfinding (Huang, Chu, Hwang, & Tsaur, 2012).
Evidence for Lateral Interactions among MNTB Neurons
Volume Transmitter Signaling Through Nitric Oxide
Direct evidence that a signal can spread laterally within the MNTB has been obtained by Steinert, Forsythe and their colleagues (Steinert et al., 2008; Steinert et al., 2011). Stimulation of the presynaptic input at a relatively low rate (100 Hz, for 500 msec, or 10 Hz for 1 hour, comparable to spontaneous in vivo rates of firing in the absence of sound stimuli) causes an increase in levels of NO and cyclic GMP in the principal neurons (Steinert et al., 2008; Steinert et al., 2011). These increases occur both in the neurons that receive a direct synaptic input, and in those that are located in adjacent regions but which are not stimulated synaptically. Extracellular application of an NO scavenger does not block the increase in neurons that receive the synaptic input, but completely prevents it in neurons not receiving a direct input (Figure 8). These and other experiments have established that, once generated by a synaptic stimulus, NO acts as volume transmitter that diffuses throughout the MNTB to influence the properties of neighboring neurons (Steinert et al., 2008).
As stated earlier, two of the effects of NO on MNTB neurons are to reduce Kv3.1b potassium currents and to increase Kv2 potassium currents (Steinert et al., 2008; Steinert et al., 2011). These actions are believed to act primarily through dephosphorylation of the channels or related components following activation of a PP2A-like protein phosphatase, most likely mediated by a NO-dependent activation of PKG, the cyclic GMP-dependent protein kinase (Moreno, Vega-Saenz de Miera, Nadal, Amarillo, & Rudy, 2001). Such mechanisms could also therefore contribute much longer-term changes in channel expression.
Transcription Is Coordinated in Groups of Adjacent MNTB Neurons
The promoter that regulates the transcription of the Kv3.1 channel gene contains a cyclic AMP/Ca2+-response element (CRE; Gan & Kaczmarek, 1998; Gan et al., 1996). This element is activated on binding phosphorylated transcription factor CREB (cAMP response element-binding protein). Phosphorylation of CREB occurs during stimulation that elevates intracellular cyclic AMP or Ca2+ levels, leading to synthesis of messenger RNA encoding Kv3.1 (Gan et al., 1996). Immunostaining for phosphorylated CREB (pCREB) in the MNTB therefore provides a picture of which cells are likely to be actively transcribing CRE-regulated genes such as that for Kv3.1.
Levels of CREB do not vary significantly across the medial-lateral tonotopic axis of the MNTB (von Hehn et al., 2004). Phosphorylation of CREB, however, appears to be an “all or none” event in the nucleus of each neuron. In some neurons, nuclei are heavily stained for pCREB, while others have no detectable phosphorylation of this transcription factor. In animals with normal hearing, however, neurons with high pCREB are found adjacent to each other. One or more large clusters pCREB-positive neurons are found along the tonotopic axis, separated by regions devoid of pCREB staining (Figure 9A). An interesting aspect of these pCREB-positive clusters is that they can be found in different locations along the tonotopic axis even in animals maintained in similar auditory environments. The lower panels in Figure 9A show examples of immunostaining, represented as “bar codes,” in which the major clusters of pCREB-positive neurons are found in the lateral, central or medial aspects of the MNTB.
The clustering of pCREB-positive neurons along the tonotopic axis depends on ongoing activity in the auditory system (von Hehn et al., 2004). In the BL/6 strain of mice, which lose hearing after several months of age, the clusters are present at 6 weeks of age, but at 8 months immunostaining occurs apparently randomly across the tonotopic axis (Figure 9B, C) and this is correlated with the disappearance of the gradient in the Kv3.1 channel itself (see Figure 4; von Hehn et al., 2004).
The simplest explanation for the existence of pCREB-positive clusters of neurons in the MNTB is that these are produced by lateral interactions between MNTB neurons and that these are shaped by synaptic inputs, which regulate the transcription of mRNA for Kv3.1 in adjacent set of neurons. The fact that these clusters are found in different places along the tonotopic axis in different animals suggests that they represent an ongoing adaptation to the auditory environment.
What Are Potential Mechanisms for Interactions among MNTB Neurons that Establish Levels of K+ Channels?
1. Local release of transmitter and other components: As shown in Figure 8, there is good evidence that at least one substance, NO, acts as a local volume transmitter in the MNTB to modulate potassium channels in adjacent neurons (Steinert et al., 2008; Steinert et al., 2011). In addition, it is known that, during development, neurotransmitter released at the terminals of MNTB neurons can spillover to act on the axons of adjacent MNTB neurons, providing another potential way for these cells to communicate with each other directly (Weisz, Rubio, Givens, & Kandler, 2016). Recent studies have also demonstrated that cells are capable of releasing many other substances in the external medium. These include exosomes, which are extracellular vesicles that are first formed as multivesicular bodies within the cytoplasm and then ejected from the cell (Edgar, 2016). These exosomes can be taken up by other cells and they provide a mechanism for the transfer or proteins, lipids, mRNAs and other large molecules from one cell to its neighbors. As of now, the existence of this mechanism has not be tested in the MNTB.
2. Direct synaptic connections: A proportion of MNTB neurons have recurrent collateral axons that branch off the main axon near its target in the LSO, and project back to the MNTB (Dondzillo, Thompson, & Klug, 2016; Kuwabara & Zook, 1991). These fibers terminate near the dendrites of the same cells but also provide inhibitory input to nearby principal neurons. It has been estimated that up to one third of MNTB neurons have such collateral fibers (Dondzillo et al., 2016). Such lateral inhibition could provide side band inhibition that would enhance the frequency tuning of MNTB neurons. If such glycinergic inhibition is also coupled to mechanisms that modulate the synthesis or activity of K+ channels, however, this would provide the needed transfer of information to establish gradients or other patterns of channel expression across the nucleus.
In theory, other inputs to the MNTB, such as glycinergic inputs from the ventral nucleus of the trapezoid body (Albrecht, Dondzillo, Mayer, Thompson, & Klug, 2014; Mayer, Albrecht, Dondzillo, & Klug, 2014), perhaps shaped by inputs from higher centers, could also mediate lateral interactions between neurons in the MNTB to influence channel expression.
3. Neuron-glial cell interactions: At least two types of glial cells in the MNTB are influenced by synaptic inputs. The cell bodies of the principal neurons of the MNTB, and the presynaptic calyces of Held are surrounded by astrocytes, which may completely envelop these presynaptic terminals (Reyes-Haro et al., 2010). Stimulation of the presynaptic fibers evokes inward currents these glial cells, and can elevate internal Ca2+ levels. The processes of astrocytes make contact with several different MNTB principal neurons, and spontaneous calcium transients in the astrocytes produce slow NMDA-mediated inward currents in the neurons (Reyes-Haro et al., 2010). A second type of glial cell, characterized by its expression of the proteoglycan NG2, receives direct AMPA receptor-mediated synaptic inputs from the calyx of Held presynaptic terminals, and these inputs are synchronized in time to the neuronal inputs (Muller et al., 2009). Thus glial cell-mediated interactions provide a potential mechanism for mediating local interactions in the MNTB.
Neurons in the MNTB, as well as the presynaptic terminals that contact them, express a variety of different types of K+ channel subunits. The level of any specific subunits varies from neuron to neuron, and, for many of the subunits, a tonotopic gradient of expression exists within the nucleus. As a result, some MNTB neurons have a complement of subunits that favors rapid firing with lower temporal accuracy, while the mix of channels in other neurons favors accurate phase-locking. The activity of different channel subunits is, however, subject to very rapid modulation by auditory stimuli. The rate at which different channels are synthesized is also regulated by the auditory environment. These findings indicate that modulation of K+ channels in individual neurons will alter specific aspects of a sound stimulus to which the neuron responds. If such modulation were to be coordinated among groups of MNTB neurons, through direct or indirect lateral interactions between the neurons, this would allow the ensemble of neurons to extract the maximal amount of information about the timing and intensity of auditory stimuli. Similar modulation of ion channels is likely to play a role at all levels of auditory processing.
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