Interaction of Kv3 Potassium Channels and Resurgent Sodium Current Influences the Rate of Spontaneous Firing of Purkinje Neurons

Akemann, Walther; Knöpfel, Thomas

doi:10.1523/jneurosci.5204-05.2006

Cited by 119 publications

(134 citation statements)

References 54 publications

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“…FSNs, including PCs, require channels with special functional features, such as Kv3 voltage-dependent K + channels (Rudy and McBain, 2001;Akemann and Knopfel, 2006). In agreement with previous studies (Sacco and Tempia, 2002;Martina et al, 2003;McKay and Turner, 2004), we show that PCs express very large voltagedependent and Ca 2+ independent K + currents sensitive to submillimolar doses of TEA.…”

Section: Discussionsupporting

confidence: 92%

“…These two goals are attained by the exploitation of two highly specialized ion channels (Akemann and Knopfel, 2006): i) a resurgent Na + channel with an extremely fast recovery from inactivation, due to an unusual mechanism based on a peptide-mediated channel block, identified as the β 4 subunit (Grieco et al, 2005) but also mimicked by an exogenously applied peptide toxin (Schiavon et al, 2006); ii) K + channels of a subfamily (Kv3 or KCNC), which have very fast activation and deactivation kinetics associated with a high threshold for activation (Rudy and McBain, 2001). These properties of Kv3 channels cause a very fast action potential repolarization followed by a brief afterhyperpolarization, which allows a rapid recovery of Na + channels from inactivation.…”

Section: Introductionmentioning

confidence: 99%

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Properties and expression of Kv3 channels in cerebellar Purkinje cells

Sacco

Luca

Tempia

2006

Molecular and Cellular Neuroscience

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In cerebellar Purkinje cells, Kv3 potassium channels are indispensable for firing at high frequencies. In Purkinje cells from young mice (P4-P7), Kv3 currents, recorded in whole-cell in slices, activated at −30 mV, with rapid activation and deactivation kinetics, and they were partially blocked by blood depressing substance-I (BDS-I, 1 μM). At positive potentials, Kv3 currents were slowly but completely inactivating, while the recovery from inactivation was about eightfold slower, suggesting that a previous firing activity or a small change of the resting potential could in principle accumulate inactivated Kv3 channels, thereby finely tuning Kv3 current availability for subsequent action potentials. Single-cell RT-PCR analysis showed the expression by all Purkinje cells (n = 10 for each subunit) of Kv3.1, Kv3.3 and Kv3.4 mRNA, while Kv3.2 was not expressed. These results add to the framework for interpreting the physiological function and the molecular determinants of Kv3 currents in cerebellar Purkinje cells.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Properties and expression of Kv3 channels in cerebellar Purkinje cells

Sacco

Luca

Tempia

2006

Molecular and Cellular Neuroscience

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“…Potential concomitant alterations in complex spikes, however, were not explored despite the fact both channels affect complex spikes. The interspike interval variability is normal in Kcnc3-null mice (Akemann and Knöpfel, 2006). Purkinje-cell-specific ablation of the sodium channel Nav1.6 caused ataxia and virtually abrogated spontaneous simple spikes (Levin et al, 2006).…”

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

confidence: 99%

“…Unless postsynaptic neurons adapt, tonic inhibition by simple spikes and compound IPSPs triggered by complex spikes, despite the reduced spikelet number and intraburst frequency, might be augmented overall. Alternatively, the net effect might be decreased inhibition, for the frequencies of simple spikes (Akemann and Knöpfel, 2006) as well as spikes within complex spike bursts are both diminished, and complex spikes contain fewer spikelets. Interestingly, the magnitude of the effect of Kv3.3 loss on simple spike frequency, a ϳ40% reduction, is less than that on the intraburst frequency of complex spikes, a ϳ70% reduction, consistent with higher frequency firing being more acutely sensitive to the absence of .…”

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

J. Neurosci.

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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...

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“…Kv3.3, like other Kv3 channels, has specialized gating properties that promote sustained, high-frequency firing in neurons (58). In cerebellar Purkinje neurons, Kv3.3 contributes to spontaneous pace-making activity (59,60). Interestingly, dominant gain-of-function mutations that alter the specialized gating properties of Kv3.3 channels cause infantonset spinocerebellar ataxia type 13 characterized by substantial cerebellar atrophy in the first few years of life, motor delay, persistent locomotor deficits, and intellectual disability (61)(62)(63).…”

Section: Dominant Gain-of-function Gating Mutations Are Associated Withmentioning

confidence: 99%

Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening

Lin

Cannon

Papazian

2018

Proc. Natl. Acad. Sci. U.S.A.

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A de novo mutation in the KCND2 gene, which encodes the Kv4.2 K + channel, was identified in twin boys with intractable, infantonset epilepsy and autism. Kv4.2 channels undergo closed-state inactivation (CSI), a mechanism by which channels inactivate without opening during subthreshold depolarizations. CSI dynamically modulates neuronal excitability and action potential back propagation in response to excitatory synaptic input, controlling Ca 2+ influx into dendrites and regulating spike timing-dependent plasticity. Here, we show that the V404M mutation specifically affects the mechanism of CSI, enhancing the inactivation of channels that have not opened while dramatically impairing the inactivation of channels that have opened. The mutation gives rise to these opposing effects by increasing the stability of the inactivated state and in parallel, profoundly slowing the closure of open channels, which according to our data, is required for CSI. The larger volume of methionine compared with valine is a major factor underlying altered inactivation gating. Our results suggest that V404M increases the strength of the physical interaction between the pore gate and the voltage sensor regardless of whether the gate is open or closed. Furthermore, in contrast to previous proposals, our data strongly suggest that physical coupling between the voltage sensor and the pore gate is maintained in the inactivated state. The state-dependent effects of V404M on CSI are expected to disturb the regulation of neuronal excitability and the induction of spike timing-dependent plasticity.Our results strongly support a role for altered CSI gating in the etiology of epilepsy and autism in the affected twins.ecently, a de novo mutation in the KCND2 gene was identified by exome sequencing in monozygotic twin boys with intractable seizures starting in infancy, autism, and intellectual disability (1). KCND2 encodes the Kv4.2 voltage-gated K + channel. Kv4.2 and other members of the Kv4 family serve as the pore-forming subunits in inactivating, somatodendritic A-type K + (I SA ) channels, which are widely expressed in the brain (2-8). Kv4.2 is the sole pore-forming subunit in I SA channels found in pyramidal cells in the CA1 region of the hippocampus (6, 7). The hallmark property of I SA channels is the ability to inactivate without opening during subthreshold excitatory postsynaptic potentials (5,8,9). This occurs through the mechanism of closedstate inactivation (CSI) (5, 10). CSI determines the steady-state availability of I SA channels and thereby controls resting excitability and firing frequency (5,8,9). In addition, CSI temporarily increases excitability in response to excitatory synaptic input, boosting the back propagation of action potentials and Ca 2+ influx into dendrites (7,(11)(12)(13)(14)(15)(16)(17). As a result, CSI is a key component in mechanisms of spike timing-dependent synaptic plasticity (13, 17). We previously reported that V404M, the Kv4.2 mutation associated with epilepsy and autism, impairs CSI, but the underlying m...

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Interaction of Kv3 Potassium Channels and Resurgent Sodium Current Influences the Rate of Spontaneous Firing of Purkinje Neurons

Cited by 119 publications

References 54 publications

Properties and expression of Kv3 channels in cerebellar Purkinje cells

Properties and expression of Kv3 channels in cerebellar Purkinje cells

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

Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening

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