Disruption of the Epilepsy KCNQ2 Gene Results in Neural Hyperexcitability

Watanabe, Hirotaka; Nagata, Eiichiro; Kosakai, Arifumi; Nakamura, Motonao; Yokoyama, M.; Tanaka, Kortaro; Sasai, Hisanori

doi:10.1046/j.1471-4159.2000.0750028.x

Cited by 178 publications

(140 citation statements)

References 21 publications

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“…In a phenotype similar to that of a previous Kcnq2 knock-out model (Watanabe et al, 2000), Szt1/Szt1 mice die of lung atelectasis shortly after birth. Szt1/ϩ mice are viable and display decreased seizure threshold and altered sensitivity to drugs that modify the M-channel (Otto et al, 2004), but the specific contribution of the Kcnq2 component of this deletion has not been characterized.…”

Section: Introductionsupporting

confidence: 60%

A Spontaneous Mutation InvolvingKcnq2(Kv7.2) Reduces M-Current Density and Spike Frequency Adaptation in Mouse CA1 Neurons

Otto¹,

Yang²,

Frankel³

et al. 2006

J. Neurosci.

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The M-type K ϩ current [I K(M) ] activates in response to membrane depolarization and regulates neuronal excitability. Mutations in two subunits (KCNQ2 and KCNQ3; Kv7.2 and Kv7.3) that underlie the M-channel cause the human seizure disorder benign familial neonatal convulsions (BFNC), presumably by reducing I K(M) function. In mice, the Szt1 mutation, which deletes the genomic DNA encoding the KCNQ2 C terminus and all of CHRNA4 (nicotinic acetylcholine receptor ␣4 subunit) and ARFGAP-1 (GTPase-activating protein that inactivates ADP-ribosylation factor 1), reduces seizure threshold, and alters M-channel pharmacosensitivity. Genomic deletions affecting the C terminus of KCNQ2 have been identified in human families with BFNC, and truncation of the C terminus prevents proper KCNQ2/KCNQ3 channel assembly in Xenopus oocytes. We showed previously that Szt1 mice have a reduced baseline seizure threshold and altered sensitivity to drugs that act at the M-channel. Specifically, the proconvulsant M-channel blocker linopirdine and anticonvulsant enhancer retigabine display increased and decreased potency, respectively, in Szt1 mice. To investigate the effects of the Szt1 mutation on I K(M) function explicitly, perforated-patch electrophysiology was performed in CA1 pyramidal neurons of the hippocampus in brain slices prepared from C57BL/6J-Szt1/؉ and control C57BL/6Jϩ/ϩ mice. Our results show that Szt1 reduces both I K(M) amplitude and current density, inhibits spike frequency adaptation, and alters many aspects of M-channel pharmacology. This is the first evidence that a naturally occurring Kcnq2 mutation diminishes the amplitude and function of the native neuronal I K(M) , resulting in significantly increased neuronal excitability. Finally, the changes in single-cell biophysical properties likely underlie the altered seizure threshold and pharmacosensitivity reported previously in Szt1 mice.

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Section: Introductionsupporting

confidence: 60%

A Spontaneous Mutation InvolvingKcnq2(Kv7.2) Reduces M-Current Density and Spike Frequency Adaptation in Mouse CA1 Neurons

Otto¹,

Yang²,

Frankel³

et al. 2006

J. Neurosci.

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“…118,119 In addition, mice in which a single copy of the gene for KCNQ2 was disrupted by gene targeting (Kcnq2 ϩ/Ϫ ) showed increased sensitivity to PTZ seizures. 120 The combination of KCNQ2 and KCNQ3 underlies the bulk of the Mcurrent in neurons, 121 although KCNQ5 alone or in combination with KCNQ3 can also contribute to M-current. It is believed that M-current regulates neuronal excitability by determining the neuronal firing threshold, influencing the firing rate, and modulating neuronal responsiveness to synaptic inputs.…”

Section: Voltage-gated Potassium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…We first focused on KCNQ3 knockout mice (KCNQ3 Ϫ/Ϫ ). These mice were viable, unlike KCNQ2 knockouts (8), and their breeding resulted in progeny that followed Mendelian inheritance (35 KCNQ3 ϩ/ϩ , 72 KCNQ3 ϩ/Ϫ , 34 KCNQ3 Ϫ/Ϫ , n ϭ 21 litters, 141 mice, 2 P ϭ 0.96). As this was not the focus of our study, we did not characterize the mice for any neurological phenotypes.…”

Section: Role Of Kcnq3 In the Imahp In Hippocampusmentioning

confidence: 99%

“…To test this hypothesis, we obtained mice genetically deficient for KCNQ2. KCNQ2 Ϫ/Ϫ mice do not survive because of pulmonary atelectasis; therefore, we investigated KCNQ2 ϩ/Ϫ mice, which have a decreased threshold for chemically induced seizures (8). We found that the peak amplitude of the ImAHP was significantly decreased in KCNQ2 ϩ/Ϫ dentate granule cells compared to KCNQ2 ϩ/ϩ littermates (KCNQ2 ϩ/ϩ : 199 Ϯ 19 pA, n ϭ 7; KCNQ2 ϩ/Ϫ : 81 Ϯ 16 pA, n ϭ 10; P Ͻ 0.0005) (Fig.…”

Section: Contribution Of Kcnq2 To Imahp In Hippocampusmentioning

confidence: 99%

Contribution of KCNQ2 and KCNQ3 to the medium and slow afterhyperpolarization currents

Tzingounis

Nicoll

2008

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

125

143

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Benign familial neonatal convulsion (BNFC) is a neurological disorder caused by mutations in the potassium channel genes KCNQ2 and KCNQ3, which are thought to contribute to the medium afterhyperpolarization (mAHP). Despite their importance in normal brain function, it is unknown whether they invariably function as heteromeric complexes. Here, we examined the contribution of KCNQ3 and KCNQ2 in mediating the apamin-insensitive mAHP current (ImAHP) in hippocampus. The ImAHP was not impaired in CA1 pyramidal neurons from mice genetically deficient for either KCNQ3 or KCNQ2 but was reduced Ϸ50% in dentate granule cells. While recording from KCNQ-deficient mice, we observed that the calcium-activated slow afterhyperpolarization current (IsAHP) was also reduced in dentate granule cells, suggesting that KCNQ channels might also contribute to this potassium current whose molecular identity is unknown. Further pharmacological and molecular experiments manipulating KCNQ channels provided evidence in support of this possibility. Together our data suggest that multiple KCNQ subunit compositions can mediate the ImAHP, and that the very same subunits may also contribute to the IsAHP. We also present data suggesting that the neuronal calcium sensor protein hippocalcin may allow for these dual signaling processes.Epilepsy ͉ KCNQ ͉ M-current ͉ Retigabine ͉ sAHP

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Disruption of the Epilepsy KCNQ2 Gene Results in Neural Hyperexcitability

Cited by 178 publications

References 21 publications

A Spontaneous Mutation InvolvingKcnq2(Kv7.2) Reduces M-Current Density and Spike Frequency Adaptation in Mouse CA1 Neurons

A Spontaneous Mutation InvolvingKcnq2(Kv7.2) Reduces M-Current Density and Spike Frequency Adaptation in Mouse CA1 Neurons

Molecular Targets for Antiepileptic Drug Development

Contribution of KCNQ2 and KCNQ3 to the medium and slow afterhyperpolarization currents

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