Distribution of Kv3.3 potassium channel subunits in distinct neuronal populations of mouse brain

The fast-activating/deactivating voltage-gated potassium channel Kv3.3 (Kcnc3) is expressed in various neuronal cell types involved in motor function, including cerebellar Purkinje cells. Spinocerebellar ataxia type 13 (SCA13) patients carrying dominant-negative mutations in Kcnc3 and Kcnc3-null mutant mice both display motor incoordination, suggested in mice by increased lateral deviation while ambulating and slips on a narrow beam. Motor skill learning, however, is spared. Mice lacking Kcnc3 also exhibit muscle twitches. In addition to broadened spikes, recordings of Kcnc3-null Purkinje cells revealed fewer spikelets in complex spikes and a lower intraburst frequency. Targeted reexpression of Kv3.3 channels exclusively in Purkinje cells in Kcnc3-null mice as well as in mice also heterozygous for Kv3.1 sufficed to restore simple spike brevity along with normal complex spikes and to rescue specifically coordination. Therefore, spike parameters requiring Kv3.3 function in Purkinje cells are involved in the ataxic null phenotype and motor coordination, but not motor learning.Key words: K channels; burst firing; motor dysfunction; cerebellum; Purkinje cell; complex spike IntroductionVoltage-gated potassium (Kv) channels of the Kv3 subfamily enable neurons to fire narrow action potentials at high frequencies beyond ϳ200 Hz. Four separate genes (Kcnc1-Kcnc4 ) encoding subunits Kv3.1-Kv3.4 are expressed in various combinations in CNS neurons in which they assemble into homotetrameric and heterotetrameric channels. Mice lacking the Kcnc3-encoded Kv3.3 subunit exhibit motor deficits manifested as increased lateral deviation while ambulating and increased slips while traversing a narrow beam (McMahon et al., 2004;Joho et al., 2006b). A role for Kv3.3 channels in motor coordination is also underscored by the recent finding that dominant-negative mutations found in the human KCNC3 gene correlate with the neurological disorder spinocerebellar ataxia 13 (Waters et al., 2006). Kv3-type channels are distinguished by exceptionally rapid kinetics of activation and deactivation, rendering them ideally suited to drive repolarization that is rapid, both in its onset and relief, so that the next action potential upstroke can occur with minimal delay in the absence of lingering afterhyperpolarization. High-frequency spiking is facilitated by both minimizing sodium channel inactivation through brief action potentials and by promoting sodium channel deinactivation through the excursion to negative potentials during the fast afterhyperpolarization. Indeed, the loss of Kv3-type channels results in broadened spikes accompanied by decelerated firing (Rudy and McBain, 2001). Unlike most other neuron types in which Kv3.3 subunits are expressed with other Kv3-type subunits, Purkinje cells express high levels of Kv3.3 and lower levels of Kv3.4 (Weiser et al., 1994;Martina et al., 2003). Loss of Kv3.3 results in a doubling of action potential duration (McMahon et al., 2004). Furthermore, blockade with tetraethylammonium (TEA) or BDS-I at a conc...

Section: Perturbed Complex Spikes: Potential Impact On Deep Nuclear Nmentioning

confidence: 90%

“…Large glutamatergic neurons of the DCN express Kv3.1 and Kv3.3 (McMahon et al, 2004;Chang et al, 2007), suggesting functional redundancy. The cell types that express Kv3.2 in the DCN remain unidentified.…”

Section: Perturbed Complex Spikes: Potential Impact On Deep Nuclear Nmentioning

confidence: 99%

Purkinje-Cell-Restricted Restoration of Kv3.3 Function Restores Complex Spikes and Rescues Motor Coordination inKcnc3Mutants

Hurlock

McMahon²,

Joho³

2008

“…An absence of membrane accumulation of Kv3.2 and Kv3.4 cannot be explained by failure to detect a specific splice variant because the antibodies used targeted the invariant N termini. While Kv3.1a, Kv3.1b, Kv3.2, and Kv3.3 are all present in axons or at least terminals, only Kv3.1b has been detected at nodes of Ranvier (Ozaita et al, 2002;Devaux et al, 2003;Chang et al, 2007). Thus, if Kv3.1b has an important nodal function, we might expect mice lacking only Kcnc1 to display ataxia; however, interestingly, they do not (Joho et al, 2006).…”

Section: Kv33 Expression In Purkinje Cells Is Necessary For Normal Mmentioning

confidence: 99%

“…1), the projection neurons, Purkinje cells, express Kv3.3 throughout the cell and Kv3.4 largely in dendrites (Martina et al, 2003;McMahon et al, 2004;Chang et al, 2007). Granule cells express Kv3.1 and Kv3.3 (Weiser et al, 1995;Sekirnjak et al, 1997;Ozaita et al, 2002), whereas basket cells express Kv3.2 and Kv3.4 channel subunits in the pinceaux (Veh et al, 1995;Bobik et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Rescue of Motor Coordination by Purkinje Cell-Targeted Restoration of Kv3.3 Channels inKcnc3-Null Mice RequiresKcnc1

Hurlock¹,

Bose²,

Pierce³

et al. 2009

The role of cerebellar Kv3.1 and Kv3.3 channels in motor coordination was examined with an emphasis on the deep cerebellar nuclei (DCN). Kv3 channel subunits encoded by Kcnc genes are distinguished by rapid activation and deactivation kinetics that support high-frequency, narrow action potential firing. Previously we reported that increased lateral deviation while ambulating and slips while traversing a narrow beam of ataxic Kcnc3-null mice were corrected by restoration of Kv3.3 channels specifically to Purkinje cells, whereas Kcnc3-mutant mice additionally lacking one Kcnc1 allele were partially rescued. Here, we report mice lacking all Kcnc1 and Kcnc3 alleles exhibit no such rescue. For Purkinje cell output to reach the rest of the brain it must be conveyed by neurons of the DCN or vestibular nuclei. As Kcnc1, but not Kcnc3, alleles are lost, mutant mice exhibit increasing gait ataxia accompanied by spike broadening and deceleration in DCN neurons, suggesting the facet of coordination rescued by Purkinje-cell-restricted Kv3.3 restoration in mice lacking just Kcnc3 is hypermetria, while gait ataxia emerges when additionally Kcnc1 alleles are lost. Thus, fast repolarization in Purkinje cells appears important for normal movement velocity, whereas DCN neurons are a prime candidate locus where fast repolarization is necessary for normal gait patterning.

“…Kv3-type channels are involved in the rapid repolarization of the action potential (AP), and their presence in neurons correlates with narrow APs, fast afterhyperpolarization (AHP), and highfrequency firing beyond 200 Hz. Although Kv3.1 and Kv3.3 subunits are expressed throughout the brain, their expression is restricted to distinct neuronal subpopulations (Drewe et al, 1992;Perney et al, 1992;Weiser et al, 1994Weiser et al, , 1995Sekirnjak et al, 1997;Ozaita et al, 2002;Chang et al, 2007). In neocortex, thalamus, hippocampus, and striatum, Kv3-type channels are found in GABAergic cells (mostly interneurons) that also express the calcium-binding protein parvalbumin (PV), a marker for fastspiking neurons.…”

Section: Introductionmentioning

confidence: 99%

Ablation of Kv3.1 and Kv3.3 Potassium Channels Disrupts Thalamocortical OscillationsIn VitroandIn Vivo

Espinosa

Torres-Vega

Marks³

et al. 2008

The genes Kcnc1 and Kcnc3 encode the subunits for the fast-activating/fast-deactivating, voltage-gated potassium channels Kv3.1 and Kv3.3, which are expressed in several brain regions known to be involved in the regulation of the sleep-wake cycle. When these genes are genetically eliminated, Kv3.1/Kv3.3-deficient mice display severe sleep loss as a result of unstable slow-wave sleep. Within the thalamocortical circuitry, Kv3.1 and Kv3.3 subunits are highly expressed in the thalamic reticular nucleus (TRN), which is thought to act as a pacemaker at sleep onset and to be involved in slow oscillatory activity (spindle waves) during slow-wave sleep. We showed that in cortical electroencephalographic recordings of freely moving Kv3.1/Kv3.3-deficient mice, spectral power is reduced up to 70% at frequencies Ͻ15 Hz. In addition, the number of sleep spindles in vivo as well as rhythmic rebound firing of TRN neurons in vitro is diminished in mutant mice. Kv3.1/Kv3.3-deficient TRN neurons studied in vitro show ϳ60% increase in action potential duration and a reduction in highfrequency firing after depolarizing current injections and during rebound burst firing. The results support the hypothesis that altered electrophysiological properties of TRN neurons contribute to the reduced EEG power at slow frequencies in the thalamocortical network of Kv3-deficient mice.