Genetic perturbations suggest a role of the resting potential in regulating the expression of the ion channels of the KCNA and HCN families in octopus cells of the ventral cochlear nucleus

Abstract

Low-voltage-activated K+ (gKL) and hyperpolarization-activated mixed cation conductances (gh) mediate currents, IKL and Ih, through channels of the Kv1 (KCNA) and HCN families respectively and give auditory neurons the temporal precision required for signaling information about the onset, fine structure, and time of arrival of sounds. Being partially activated at rest, gKL and gh contribute to the resting potential and shape responses to even small subthreshold synaptic currents. Resting gKL and gh also affect the coupling of somatic depolarization with the generation of action potentials. To learn how these important conductances are regulated we have investigated how genetic perturbations affect their expression in octopus cells of the ventral cochlear nucleus (VCN). We report five new findings: First, the magnitude of gh and gKL varied over more than two-fold between wild type strains of mice. Second, average resting potentials are not different in different strains of mice even in the face of large differences in average gKL and gh. Third, IKL has two components, one being α-dendrotoxin (α-DTX)-sensitive and partially inactivating and the other being α-DTX-insensitive, tetraethylammonium (TEA)-sensitive, and non-inactivating. Fourth, the loss of Kv1.1 results in diminution of the α-DTX-sensitive IKL, and compensatory increased expression of an α-DTX-insensitive, tetraethylammonium (TEA)-sensitive IKL. Fifth, Ih and IKL are balanced at the resting potential in all wild type and mutant octopus cells even when resting potentials vary in individual cells over nearly 10 mV, indicating that the resting potential influences the expression of gh and gKL. The independence of resting potentials on gKL and gh shows that gKL and gh do not, over days or weeks, determine the resting potential but rather that the resting potential plays a role in regulating the magnitude of either or both gKL and gh.

Cellular Computations Underlying Detection of Gaps in Sounds and Lateralizing Sound Sources

“…2, middle panels) [91]. In contrast, the loss of Kv1.1 is compensated in steady-state currents so that only the peak I KL differed between mutants and wild type [92]. …”

“…They are largest in outbred ICR mice [50, 61], smaller in HCN1 +/+ that are a mixed C57BL/6 and 129S strain [88, 91], and smallest in Kv1.1 +/+ mice that are on a C3HeB/FeJ background [87, 92]. …”

“…The large magnitude makes it possible to resolve I h and I KL at the resting potential. In wild-type octopus cells the ZD7288-sensitive I h and α-dendrotoxin-sensitive I KL are opposite and almost equal at the resting potential [13, 91, 92]. In Kcna1 −/− mice, however, the α-dendrotoxin-sensitive component of I KL balances only about half of I h .…”

“…In Kcna1 −/− mice, therefore, K + channels with a different subunit composition that are insensitive to α-dendrotoxin and that generally comprise only a minor component, compensated for the loss of Kv1.1 subunits. The finding that the voltage-sensitive I KL equals the voltage-sensitive I h equal even when resting potentials vary over a 9 mV range, suggests that the resting potential plays a role in matching the expression of g KL to balance I KL with I h at rest [92]. Our inability to resolve the small resting I h and I KL in bushy cells leaves open the question whether this rule applies beyond octopus cells.…”

“…The wild type control strains, HCN1 +/+ and Kv1.1 +/+ differed from one another. This figure includes data published previously [91, 92]. …”