A team of potassium channels tunes up auditory neurons

Mammals harbour a diverse array of voltage-gated K⁺ channels. How those channels team up in a neuron to do a job is becoming clear in the principal cells of the medial nucleus of the trapezoid body (MNTB). Ian Forsythe and his colleagues have used the electrically compact nature of MNTB neurons to measure K⁺ currents and combined those findings with molecular biological studies to identify, characterize and localize diverse K⁺ channels on MNTB neurons. A series of reports, the latest by Hardman and Forsythe being in this issue of The Journal of Physiology (Hardman & Forsythe, 2009), show that the firing of action potentials in MNTB neurons is finely controlled by a team of K⁺ conductances with different properties.

Neurons in the MNTB are part of a neuronal circuit that assesses differences in intensity at the two ears, cues that are used to determine where in the horizontal plane sounds arise (Fig. 1A). Neurons in the lateral superior olive (LSO) compare interaural intensity by summing excitation from the ipsilateral ear with inhibition from the contralateral ear. Anyone who has participated in a conversation knows that sounds change rapidly in frequency and intensity; for interaural comparisons of intensity to be useful for localizing sounds, the time of arrival of excitation and inhibition at the LSO must be matched to within a few hundred microseconds.

Figure 1. The medial nucleus of the trapezoid body (MNTB) feeds information about contralateral sounds to neurons in the lateral superior olive (LSO) that compare interaural intensity by balancing ipsilateral excitation (red) with contralateral inhibition (blue).

A, schematic representation in the coronal plane illustrating that neurons in the LSO receive acoustic input from the ipsilateral side through auditory nerve fibres (green) and neurons of the cochlear nucleus (CN). From the contralateral side, globular bushy cells of the CN relay through calyces of Held to neurons in the MNTB. B, the firing of MNTB neurons is regulated by a team of K⁺ channels in the presynaptic calyx, at the soma, initial segment and axon (colour coded).

How are the delays in ipsi- and contralateral inputs to the LSO matched in timing when path from the contralateral ear to the LSO is longer and includes an extra synapse? Neurons from the ipsilateral cochlear nucleus (CN) bring excitation to LSO neurons through relatively fine axons. Globular bushy cells from the contralateral CN, whose axons are particularly large and rapidly conducting, innervate MNTB neurons through calyces of Held. A calyx excites an MNTB neuron with a short and constant synaptic delay, generating large, suprathreshold EPSPs. The team of K⁺ channels allows MNTB neurons to relay the temporal firing pattern of globular bushy cells to contralateral LSO neurons as precisely timed, glycinergic IPSPs.

Which are the members of the team of K⁺ channels? Voltage-gated K⁺ channels are formed a tetrameric combinations of α subunits from within a class of channels (e.g. Kv1). Figure 1B summarizes what is known about the presence of various α subunits in the MNTB. (1) Channels of the Kv1 family, located in the pre- and postsynaptic axons as well as on somas of MNTB neurons, provide a prominent, rapidly activating, low-voltage-activated K⁺ current whose activation around rest shapes synaptic potentials and prevents repetitive firing in both the calyceal terminals and in MNTB neurons (Dodson et al. 2003). (2) Channels that contain Kv2.2 are prominent in the initial segments of axons of MNTB neurons. These high-voltage-activated, slowly activating and deactivating channels hyperpolarize neurons between action potentials when they fire rapidly. In promoting repolarization between action potentials, these channels enhance Na⁺ currents by removing inactivation when MNTB neurons fire rapidly (Johnston et al. 2008b). (3) Channels containing Kv3.1b mediate a prominent high-voltage-activated, rapidly activating and inactivating K⁺ current that repolarizes action potentials, making them narrow. Kv3.1b channels are in calyceal terminals as well as on the somatic membranes of MNTB neurons. When they are phosphorylated, Kv3.1b subunits have a lower open probability. Rapid firing induced by electrical stimulation or by a noisy acoustic environment causes a decrease in phosphorylation and an increase in this K⁺ current (Song et al. 2005). (4) Kv4.3 subunits have been found in the MNTB of mice but not rats (Johnston et al. 2008a). Channels of the Kv4 family mediate A-currents. These K⁺ currents inactivate rapidly at relatively hyperpolarized potentials making them transient and most evident when depolarization is preceded by hyperpolarization. This small current would be expected to shorten and diminish EPSPs early in a train but becomes inactivated with strong stimulation. (5) Now Hardman and Forsythe show that Kv11 channels encoded by an ether-à-go-go-related gene (ERG) are also present in MNTB neurons of mice. These channels inactivate more rapidly than they activate so that they conduct current mainly upon repolarization after inactivation is removed but before they deactivate. The current through ERG channels repolarizes MNTB neurons, its action being most prominent near the resting potential after a depolarization. K⁺ channels work as a team to sharpen EPSPs, to sharpen action potentials, and to assure that repolarization removes Na⁺ inactivation even during rapid firing. K⁺ channels enable MNTB neurons to fire robustly and to signal with temporal precision even when they are driven at high rates.