Unanticipated Region- and Cell-Specific Downregulation of Individual KChIP Auxiliary Subunit Isotypes in Kv4.2 Knock-Out Mouse Brain

Menegola, Milena; Trimmer, James S.

doi:10.1523/jneurosci.2783-06.2006

Cited by 67 publications

(93 citation statements)

References 18 publications

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“…Expression levels of 15 other proteins in the hippocampus also were analyzed with Western blotting, including other K ϩ channel proteins potentially underlying neuronal A-type K ϩ currents: Kv4.3, Kv1.4, and Kv3.4; the H channel proteins HCN1 and HCN2; the AMPA-type glutamate receptor proteins GluR1 and GluR2/3; two membrane-anchoring proteins enriched in the postsynaptic area, SAP97 and PSD-95; and proteins that functionally or physically associate with Kv4.2 such as NCS1, DPPX, a secretory-type protein containing a pentraxin domain (PTX3), and KChIP1, KChIP2, and KChIP3 (Rhodes et al, 2004;Menegola and Trimmer, 2006 (Fig. 1 B).…”

Section: Resultsmentioning

confidence: 99%

Deletion ofKv4.2Gene Eliminates Dendritic A-Type K⁺Current and Enhances Induction of Long-Term Potentiation in Hippocampal CA1 Pyramidal Neurons

Chen¹,

Li²,

Zhao³

et al. 2006

J. Neurosci.

291

374

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Section: Resultsmentioning

confidence: 99%

Deletion ofKv4.2Gene Eliminates Dendritic A-Type K⁺Current and Enhances Induction of Long-Term Potentiation in Hippocampal CA1 Pyramidal Neurons

Chen¹,

Li²,

Zhao³

et al. 2006

J. Neurosci.

291

374

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“…It has been previously reported that Kv4.2 KO mice have decreased KChIP1-3 auxiliary subunit protein levels Menegola and Trimmer 2006), which are critical regulators of Kv4.2 activity and expression (Birnbaum et al 2004). While the role of KChIP1 and KChIP2 in behavior has not been evaluated, KChIP 3 KO mice have recently been reported to have enhanced memory in contextual fear conditioning (Alexander et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Kv4.2 knockout mice have hippocampal-dependent learning and memory deficits

Lugo

Brewster²,

Spencer³

et al. 2012

Learn. Mem.

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Kv4.2 channels contribute to the transient, outward K + current (A-type current) in hippocampal dendrites, and modulation of this current substantially alters dendritic excitability. Using Kv4.2 knockout (KO) mice, we examined the role of Kv4.2 in hippocampal-dependent learning and memory. We found that Kv4.2 KO mice showed a deficit in the learning phase of the Morris water maze (MWM) and significant impairment in the probe trial compared with wild type (WT). Kv4.2 KO mice also demonstrated a specific deficit in contextual learning in the fear-conditioning test, without impairment in the conditioned stimulus or new context condition. Kv4.2 KO mice had normal activity, anxiety levels, and prepulse inhibition compared with WT mice. A compensatory increase in tonic inhibition has been previously described in hippocampal slice recordings from Kv4.2 KO mice. In an attempt to decipher whether increased tonic inhibition contributed to the learning and memory deficits in Kv4.2 KO mice, we administered picrotoxin to block GABA A receptors (GABA A R), and thereby tonic inhibition. This manipulation had no effect on behavior in the WT or KO mice. Furthermore, total protein levels of the a5 or d GABA A R subunits, which contribute to tonic inhibition, were unchanged in hippocampus. Overall, our findings add to the growing body of evidence, suggesting an important role for Kv4.2 channels in hippocampal-dependent learning and memory.Potassium (K + ) channels within hippocampal dendrites are critical regulators of post-synaptic excitability and thereby contribute to the modulation of synaptic plasticity . In particular, the transient, rapidly activating K + current (A-type current) modulates neuronal excitability by attenuating action potential initiation and back-propagating action potentials (B-APs), which reduce excitatory synaptic events (Hoffman et al. 1997;Martina et al. 1998;Johnston et al. 2000;Cai et al. 2004). The primary mediator of the A-type current in the somatodendritic regions of hippocampal pyramidal cells are the Kv4.X-subunits, and genetic deletion of Kv4.2 channels nearly eliminates the A-type current in CA1 pyramidal cell dendrites . The localization and function of Kv4.2 channels support a role for these channels in modulating synaptic activity in the hippocampus and influencing hippocampal-dependent tasks.Kv4.2 channel proteins localize to the somatodendritic regions of hippocampal principal neurons (Baldwin et al. 1991;Sheng et al. 1992;Maletic-Savatic et al. 1995;Martina et al. 1998; Serodio and Rudy 1998), and their highest expression is found in area CA1 pyramidal cell dendrites (Rhodes et al. 2004). These channel proteins localize to dendritic spines, where their activity can be modulated through auxiliary subunits and through a number of kinases. For example, activation of PKA, PKC, and ERK can down-regulate the activity and surface expression of Kv4.2 channels, which can then increase excitability within distal dendrites of CA1 neurons (for review, see Birnbaum et al. 2004).Furthermore, alteratio...

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“…com/Electrophysiology/IChMASCOT/) and IonChannelLab (67) based on a previously published gating model for Kv4.3 expressed with KChIP1 (40). This model was modified by eliminating inactivated states I 5 and I 6 arising from the open state. Data from wild-type channels were fitted using IChMASCOT, setting the initial values of kinetic parameters to those of Beck et al (40).…”

Section: Methodsmentioning

confidence: 99%

“…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)(3)(4)(5)(6)(7)(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).…”

mentioning

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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Unanticipated Region- and Cell-Specific Downregulation of Individual KChIP Auxiliary Subunit Isotypes in Kv4.2 Knock-Out Mouse Brain

Abstract: Kv4 family voltage-gated potassium channel

Cited by 67 publications

References 18 publications

Deletion ofKv4.2Gene Eliminates Dendritic A-Type K⁺Current and Enhances Induction of Long-Term Potentiation in Hippocampal CA1 Pyramidal Neurons

Deletion ofKv4.2Gene Eliminates Dendritic A-Type K⁺Current and Enhances Induction of Long-Term Potentiation in Hippocampal CA1 Pyramidal Neurons

Kv4.2 knockout mice have hippocampal-dependent learning and memory deficits

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

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Unanticipated Region- and Cell-Specific Downregulation of Individual KChIP Auxiliary Subunit Isotypes in Kv4.2 Knock-Out Mouse Brain

Abstract: Kv4 family voltage-gated potassium channel

Cited by 67 publications

References 18 publications

Deletion ofKv4.2Gene Eliminates Dendritic A-Type K+Current and Enhances Induction of Long-Term Potentiation in Hippocampal CA1 Pyramidal Neurons

Deletion ofKv4.2Gene Eliminates Dendritic A-Type K+Current and Enhances Induction of Long-Term Potentiation in Hippocampal CA1 Pyramidal Neurons

Kv4.2 knockout mice have hippocampal-dependent learning and memory deficits

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

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Deletion ofKv4.2Gene Eliminates Dendritic A-Type K⁺Current and Enhances Induction of Long-Term Potentiation in Hippocampal CA1 Pyramidal Neurons

Deletion ofKv4.2Gene Eliminates Dendritic A-Type K⁺Current and Enhances Induction of Long-Term Potentiation in Hippocampal CA1 Pyramidal Neurons