A mouse model of episodic ataxia type-1

Herson, Paco S.; Virk, Michael S.; Rustay, Nathan R.; Bond, Chris T.; Crabbe, John C.; Adelman, John P.; Maylie, James

doi:10.1038/nn1025

Cited by 140 publications

(128 citation statements)

References 26 publications

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“…41 In one study, a mouse knock-in model of the V408A mutation was constructed by introducing the mutation by homologous recombination. 68 Homozygous V408A/V408A mice died on embryonic day 3, but heterozygous V408A/ϩ mice were viable and had stress-induced loss of coordination and showed improvement with acetazolamide similar to that seen for EA-1 in humans.…”

Section: Functional Effects Of Ea-1 Mutations In Kv11mentioning

confidence: 83%

Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy

et al. 2007

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Summary: Episodic ataxia type 1 is a paroxysmal neurological disorder characterized by short-lived attacks of recurrent midline cerebellar dysfunction and continuous motor activity. Mutations in KCN1A, the gene encoding Kv1.1, a voltage-gated neuronal potassium channel, are associated with the disorder. Although rare, the syndrome highlights the fundamental features of genetic ion-channel diseases and serves as a useful model for understanding more common paroxysmal disorders, such as epilepsy and migraine. This review examines our current understanding of episodic ataxia type 1, focusing on its clinical and genetic features, pathophysiology, and treatment.

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Section: Functional Effects Of Ea-1 Mutations In Kv11mentioning

confidence: 83%

Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy

et al. 2007

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“…Similarly, K ϩ conductances further along the axon are thought to be important for preventing aberrant triggering of APs at more distal nodes . Indeed, mutations in the juxtaparanodal subunit Kv1.1 cause spontaneous epileptic seizures, bouts of uncoordinated movement, and aberrant APs that arise spontaneously in motoneuron axons (myokymia), both in humans and transgenic mice (Adelman et al, 1995;Smart et al, 1998;Zhou et al, 1999;Herson et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

A Common Ankyrin-G-Based Mechanism Retains KCNQ and Na_VChannels at Electrically Active Domains of the Axon

et al. 2006

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KCNQ (K V 7) potassium channels underlie subthreshold M-currents that stabilize the neuronal resting potential and prevent repetitive firing of action potentials. Here, antibodies against four different KCNQ2 and KCNQ3 polypeptide epitopes show these subunits concentrated at the axonal initial segment (AIS) and node of Ranvier. AIS concentration of KCNQ2 and KCNQ3, like that of voltage-gated sodium (Na V ) channels, is abolished in ankyrin-G knock-out mice. A short motif, common to KCNQ2 and KCNQ3, mediates both in vivo ankyrin-G interaction and retention of the subunits at the AIS. This KCNQ2/KCNQ3 motif is nearly identical to the sequence on Na V ␣ subunits that serves these functions. All identified Na V and KCNQ genes of worms, insects, and molluscs lack the ankyrin-G binding motif. In contrast, vertebrate orthologs of Na V ␣ subunits, KCNQ2, and KCNQ3 (including from bony fish, birds, and mammals) all possess the motif. Thus, concerted ankyrin-G interaction with KCNQ and Na V channels appears to have arisen through convergent molecular evolution, after the division between invertebrate and vertebrate lineages, but before the appearance of the last common jawed vertebrate ancestor. This includes the historical period when myelin also evolved.

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“…By causing highly regulated, time-dependent, and localized polarization of the cell membrane, the opening of K ϩ channels mediates feedback control of excitability in a variety of cell types and conditions (1). Consequently, K ϩ channel dysfunctions can cause a range of neurological disorders (2)(3)(4)(5)(6), and drugs that target K ϩ channels hold promise for a variety of clinical applications (7).…”

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confidence: 99%

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca ²⁺ -activated K ⁺ channel deficiency

Sausbier

Hu²,

Arntz³

et al. 2004

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

374

423

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Malfunctions of potassium channels are increasingly implicated as causes of neurological disorders. However, the functional roles of the large-conductance voltage-and Ca 2؉ -activated K ؉ channel (BK channel), a unique calcium, and voltage-activated potassium channel type have remained elusive. Here we report that mice lacking BK channels (BK ؊/؊ ) show cerebellar dysfunction in the form of abnormal conditioned eye-blink reflex, abnormal locomotion and pronounced deficiency in motor coordination, which are likely consequences of cerebellar learning deficiency. At the cellular level, the BK ؊/؊ mice showed a dramatic reduction in spontaneous activity of the BK ؊/؊ cerebellar Purkinje neurons, which generate the sole output of the cerebellar cortex and, in addition, enhanced short-term depression at the only output synapses of the cerebellar cortex, in the deep cerebellar nuclei. The impairing cellular effects caused by the lack of postsynaptic BK channels were found to be due to depolarization-induced inactivation of the action potential mechanism. These results identify previously unknown roles of potassium channels in mammalian cerebellar function and motor control. In addition, they provide a previously undescribed animal model of cerebellar ataxia. P otassium channels are the largest and most diverse class of ion channels underlying electrical signaling in the brain (1). By causing highly regulated, time-dependent, and localized polarization of the cell membrane, the opening of K ϩ channels mediates feedback control of excitability in a variety of cell types and conditions (1). Consequently, K ϩ channel dysfunctions can cause a range of neurological disorders (2-6), and drugs that target K ϩ channels hold promise for a variety of clinical applications (7).Among the wide range of voltage-and calcium-gated K ϩ channel types, one stands out as unique: the large-conductance voltage-and Ca 2ϩ -activated K ϩ channel (BK channel, also termed Slo or Maxi-K) differs from all other K ϩ channels in that it can be activated by both intracellular Ca 2ϩ ions and membrane depolarization (8). These channels are widely expressed in central and peripheral neurons, as well as in other tissues (9), and are regarded as a promising drug target (10). However, the functions of the BK channels in vivo have not previously been directly tested in any vertebrate species. We therefore decided to examine the functions of these channels by inactivating the gene encoding the pore-forming channel protein. MethodsA complete description of the methods is given in Supporting Methods, which is published as supporting information on the PNAS web site.Generation of BK Channel ␣ Subunit-Deficient Mice. In the targeting vector (Fig. 5, which is published as supporting information on the PNAS web site), the pore exon was flanked by a single loxP site and a floxed neo͞tk cassette. Correctly targeted embryonic stem cells were injected into C57BL͞6 blastocysts and resulting chimeric mice mated with C57BL͞6. Homozygous BK-deficient mice (F 2 generation) ...

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A mouse model of episodic ataxia type-1

Cited by 140 publications

References 26 publications

Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy

Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy

A Common Ankyrin-G-Based Mechanism Retains KCNQ and Na_VChannels at Electrically Active Domains of the Axon

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca ²⁺ -activated K ⁺ channel deficiency

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A mouse model of episodic ataxia type-1

Cited by 140 publications

References 26 publications

Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy

Episodic Ataxia Type 1: A Neuronal Potassium Channelopathy

A Common Ankyrin-G-Based Mechanism Retains KCNQ and NaVChannels at Electrically Active Domains of the Axon

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca 2+ -activated K + channel deficiency

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A Common Ankyrin-G-Based Mechanism Retains KCNQ and Na_VChannels at Electrically Active Domains of the Axon

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca ²⁺ -activated K ⁺ channel deficiency