Sound Localization in Preweanling Mice Was More Severely Affected by Deleting the Kcna1 Gene Compared to Deleting Kcna2, and a Curious Inverted-U Course of Development That Appeared to Exceed Adult Performance Was Observed in All Groups.

The submillisecond acuity for detecting rapid spatial and temporal fluctuations in acoustic stimuli observed in humans and laboratory animals depends in part on select groups of auditory neurons that preserve synchrony from the ears to the binaural nuclei in the brainstem. These fibers have specialized synapses and axons that use a low-threshold voltage-activated outward current, IKL, conducted through Kv1 potassium ion channels. These are in turn coupled with HCN channels that express a mixed cation inward mixed current, IH, to support precise synchronized firing. The behavioral evidence is that their respective Kcna1 or HCN1 genes are absent in adult mice; the results are weak startle reflexes, slow responding to noise offsets, and poor sound localization. The present behavioral experiments were motivated by an in vitro study reporting increased IKL in an auditory nucleus in Kcna2-/- mice lacking the Kv1.2 subunit, suggesting that Kcna2-/- mice might perform better than Kcna2+/+ mice. Because Kcna2-/- mice have only a 17-18-day lifespan, we compared both preweanling Kcna2-/- vs. Kcna2+/+ mice and Kcna1-/- vs. Kcna1+/+ mice at P12-P17/18; then, the remaining mice were tested at P23/P25. Both null mutant strains had a stunted physique, but the Kcna1-/- mice had severe behavioral deficits while those in Kcna2-/- mice were relatively few and minor. The in vitro increase of IKL could have resulted from Kv1.1 subunits substituting for Kv1.2 units and the loss of the inhibitory "managerial" effect of Kv1.2 on Kv1.1. However, any increased neuronal synchronicity that accompanies increased IKL may not have been enough to affect behavior. All mice performed unusually well on the early spatial tests, but then, they fell towards adult levels. This unexpected effect may reflect a shift from summated independent monaural pathways to integrated binaural processing, as has been suggested for similar observations for human infants.

Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons.

Genes Kcna1 and Kcna2 code for the voltage-dependent potassium channel subunits Kv1.1 and Kv1.2, which are coexpressed in large axons and commonly present within the same tetramers. Both contribute to the low-voltage-activated potassium current I Kv1, which powerfully limits excitability and facilitates temporally precise transmission of information, e.g., in auditory neurons of the medial nucleus of the trapezoid body (MNTB). Kcna1-null mice lacking Kv1.1 exhibited seizure susceptibility and hyperexcitability in axons and MNTB neurons, which also had reduced I Kv1. To explore whether a lack of Kv1.2 would cause a similar phenotype, we created and characterized Kcna2-null mice (-/-). The -/- mice exhibited increased seizure susceptibility compared with their +/+ and +/- littermates, as early as P14. The mRNA for Kv1.1 and Kv1.2 increased strongly in +/+ brain stems between P7 and P14, suggesting the increasing importance of these subunits for limiting excitability. Surprisingly, MNTB neurons in brain stem slices from -/- and +/- mice were hypoexcitable despite their Kcna2 deficit, and voltage-clamped -/- MNTB neurons had enlarged I Kv1. This contrasts strikingly with the Kcna1-null MNTB phenotype. Toxin block experiments on MNTB neurons suggested Kv1.2 was present in every +/+ Kv1 channel, about 60% of +/- Kv1 channels, and no -/- Kv1 channels. Kv1 channels lacking Kv1.2 activated at abnormally negative potentials, which may explain why MNTB neurons with larger proportions of such channels had larger I Kv1. If channel voltage dependence is determined by how many Kv1.2 subunits each contains, neurons might be able to fine-tune their excitability by adjusting the Kv1.1:Kv1.2 balance rather than altering Kv1 channel density.

Systematic variation of potassium current amplitudes across the tonotopic axis of the rat medial nucleus of the trapezoid body.

Many central auditory nuclei preserve the tonotopic organization of their afferent inputs, generating a frequency "map" across the nucleus. In the medial nucleus of the trapezoid body (MNTB) the most medial neurons receive inputs corresponding to the highest frequency sounds and the most lateral neurons have the lowest characteristic frequencies. Whole-cell patch recording from MNTB principal neurons in rat brainstem slices demonstrates a corresponding tonotopic organization of voltage-gated outward potassium currents. Medial MNTB neurons had larger total outward K+ current amplitudes than lateral neurons and similar medial to-lateral gradients were observed for two K+ current subtypes distinguished by their low and high voltage activation thresholds. In contrast, a third K+ conductance with an intermediate voltage threshold and slower kinetics showed an inverse gradient (being smallest in medial MNTB). The orthogonal axes of MNTB did not exhibit potassium current gradients (dorsal-to-ventral, or rostral-to-caudal). The input resistance was unchanged across the MNTB, but a slow capacitative component was enhanced in lateral neurons. These data demonstrate that the intrinsic properties of rat MNTB neurons are tuned across the tonotopic axis so as to promote shorter action potentials, faster firing and therefore greater accuracy in transmission of auditory information in the high characteristic frequency regions.

Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1.

A low voltage-activated potassium current, IKL, is found in auditory neuron types that have low excitability and precisely preserve the temporal pattern of activity present in their presynaptic inputs. The gene Kcna1 codes for Kv1.1 potassium channel subunits, which combine in expression systems to produce channel tetramers with properties similar to those of IKL, including sensitivity to dendrotoxin (DTX). Kv1.1 is strongly expressed in neurons with IKL, including auditory neurons of the medial nucleus of the trapezoid body (MNTB). We therefore decided to investigate how the absence of Kv1.1 affected channel properties and function in MNTB neurons from mice lacking Kcna1. We used the whole cell version of the patch clamp technique to record from MNTB neurons in brainstem slices from Kcna1-null (-/-) mice and their wild-type (+/+) and heterozygous (+/-) littermates. There was an IKL in voltage-clamped -/- MNTB neurons, but it was about half the amplitude of the IKL in +/+ neurons, with otherwise similar properties. Consistent with this, -/- MNTB neurons were more excitable than their +/+ counterparts; they fired more than twice as many action potentials (APs) during current steps, and the threshold current amplitude required to generate an AP was roughly halved. +/- MNTB neurons had excitability and IKL amplitudes identical to the +/+ neurons. The IKL remaining in -/- neurons was blocked by DTX, suggesting the underlying channels contained subunits Kv1.2 and/or Kv1.6 (also DTX-sensitive). DTX increased excitability further in the already hyperexcitable -/- MNTB neurons, suggesting that -/- IKL limited excitability despite its reduced amplitude in the absence of Kv1.1 subunits.