Attenuating M‐current suppression in vivo by a mutant <i>Kcnq2</i> gene knock‐in reduces seizure burden and prevents status epilepticus–induced neuronal death and epileptogenesis

Greene, Derek L.; Kosenko, Anastasia; Hoshi, Naoto

doi:10.1111/epi.14541

Cited by 22 publications

(20 citation statements)

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“…The p.(Ile205Val) variant was transfected into the mouse pyramidal neurons using in utero electroporation, and it induced an increase in excitability, 27 similar to the depletion of Kcnq2 from the same cells. Recently, homozygous mice carrying the p.(Ser559Ala) variant, involved in phosphorylation of Kcnq2 by protein kinase C, 28 were shown to have better resistance to chemically induced seizures and preserved neuronal integrity.…”

Section: Discussionmentioning

confidence: 99%

A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment

et al. 2020

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractObjective: Early onset epileptic encephalopathy with suppression-burst is one of the most severe epilepsy phenotypes in human patients. A significant proportion of cases have a genetic origin, and the most frequently mutated gene is KCNQ2, encoding Kv7.2, a voltage-dependent potassium channel subunit, leading to so-called KCNQ2related epileptic encephalopathy (KCNQ2-REE). To study the pathophysiology of KCNQ2-REE in detail and to provide a relevant preclinical model, we generated and described a knock-in mouse model carrying the recurrent p.(Thr274Met) variant. Methods: We introduced the p.(Thr274Met) variant by homologous recombination in embryonic stem cells, injected into C57Bl/6N blastocysts and implanted in pseudopregnant mice. Mice were then bred with 129Sv Cre-deleter to generate heterozygous mice carrying the p.(Thr274Met), and animals were maintained on the 129Sv genetic background. We studied the development of this new model and performed in vivo electroencephalographic (EEG) recordings, neuroanatomical studies at different time points, and multiple behavioral tests. Results: The Kcnq2 Thr274Met/+ mice are viable and display generalized spontaneous seizures first observed between postnatal day 20 (P20) and P30. In vivo EEG recordings show that the paroxysmal events observed macroscopically are epileptic seizures. The brain of the Kcnq2 Thr274Met/+ animals does not display major structural defects, similar to humans, and their body weight is normal. Kcnq2 Thr274Met/+ mice have a reduced life span, with a peak of unexpected death occurring for 25% of the animals by 3 months of age. Epileptic seizures were generally not observed when animals grew older. Behavioral characterization reveals important deficits in spatial learning and memory in adults but no gross abnormality during early neurosensory development. | 869 MILH et aL.

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Section: Discussionmentioning

confidence: 99%

A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment

et al. 2020

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“…Interestingly, we also observed an increase in the number of cFos+ hilar neurons after pilocarpine ( p = .026, n = 4–5) (Figure b). Despite the lack of overt tonic–clonic seizures from animals in this model, these findings demonstrate significant neuronal activation in response to sub‐seizure chemoconvulsant stimulation (Greene et al, ; Harvey & Sloviter, ). Previous work has demonstrated robust cFos activity in neurons of DG and hilus 15 min–2 hr after seizures in mice (Barton, Klein, Wolf, & Whit, ; Peng & Houser, ).…”

Section: Resultsmentioning

confidence: 77%

“…Mutations in KCNQ2 and KCNQ3 subunits are responsible for the generation of some inherited forms of epileptic encephalopathies (Biervert et al, ; Miceli et al, ; Singh et al, 1998). Similarly, transgenic suppression of M channels in mice results in epileptic phenotypes (Greene, Kosenko, & Hoshi, ; Niday et al, 2017; Peters, Hu, Pongs, Storm, & Isbrandt, ; Singh et al, 2008; Soh, Pant, LoTurco, & Tzingounis, ). Whereas the role of M channels in acquired epileptogenesis has not been well characterized, evidence suggests that M‐channel openers can serve a protective role in preventing seizures and other insults that can progress to epilepsy, such as stroke and traumatic brain injury (Bierbower, Choveau, Lechleiter, & Shapiro, ; Sampath, Valdez, White, & Raol, ; Vigil et al, ).…”

Section: Introductionmentioning

confidence: 99%

Functional responses of the hippocampus to hyperexcitability depend on directed, neuron‐specific KCNQ2 K⁺ channel plasticity

et al. 2019

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M-type (KCNQ2/3) K + channels play dominant roles in regulation of active and passive neuronal discharge properties such as resting membrane potential, spike-frequency adaptation, and hyper-excitatory states. However, plasticity of M-channel expression and function in nongenetic forms of epileptogenesis are still not well understood. Using transgenic mice with an EGFP reporter to detect expression maps of KCNQ2 mRNA, we assayed hyperexcitability-induced alterations in KCNQ2 transcription across subregions of the hippocampus. Pilocarpine and pentylenetetrazol chemoconvulsant models of seizure induction were used, and brain tissue examined 48 hr later. We observed increases in KCNQ2 mRNA in CA1 and CA3 pyramidal neurons after chemoconvulsantinduced hyperexcitability at 48 hr, but no significant change was observed in dentate gyrus (DG) granule cells. Using chromogenic in situ hybridization assays, changes to KCNQ3 transcription were not detected after hyper-excitation challenge, but the results for KCNQ2 paralleled those using the KCNQ2-mRNA reporter mice. In mice 7 days after pilocarpine challenge, levels of KCNQ2 mRNA were similar in all regions to those from control mice. In brain-slice electrophysiology recordings, CA1 pyramidal neurons demonstrated increased M-current amplitudes 48 hr after hyperexcitability; however, there were no significant changes to DG granule cell M-current amplitude. Traumatic brain injury induced significantly greater KCNQ2 expression in the hippocampal hemisphere that was ipsilateral to the trauma. In vivo, after a secondary challenge with subconvulsant dose of pentylenetetrazole, control mice were susceptible to tonicclonic seizures, whereas mice administered the M-channel opener retigabine were protected from such seizures. This study demonstrates that increased excitatory activity promotes KCNQ2 upregulation in the hippocampus in a cell-type specific manner. Such novel ion channel expressional plasticity may serve as a compensatory mechanism after a hyperexcitable event, at least in the short term. The upregulation described could be potentially leveraged in anticonvulsant enhancement of KCNQ2 channels as therapeutic target for preventing onset of epileptogenic seizures.

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“…Valproic acid (VPA) is an anti-epileptic agent commonly used in the clinic as a mood stabilizer for treatment of patients with bipolar disorder (Chiu et al, 2013;Cipriani et al, 2013). Using in vitro and in vivo mice models, part of the antiepileptic effect of VPA was shown to be due to inhibition of muscarinicinduced suppression of M current and to be dependent of K v 7.2 phosphorylation at S558 (Kay et al, 2015;Greene et al, 2018). It is possible that the beneficial effect of VPA as a mood stabilizer may also be related to drug-induced M-current increases.…”

Section: Bipolar Disordermentioning

confidence: 99%

Pharmacological Manipulation of Kv7 Channels as a New Therapeutic Tool for Multiple Brain Disorders

Vigil¹,

Carver²,

Shapiro³

2020

Front. Physiol.

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K v 7 ("M-type," KCNQ) K + currents, play dominant roles in controlling neuronal excitability. They act as a "brake" against hyperexcitable states in the central and peripheral nervous systems. Pharmacological augmentation of M current has been developed for controlling epileptic seizures, although current pharmacological tools are uneven in practical usefulness. Lately, however, M-current "opener" compounds have been suggested to be efficacious in preventing brain damage after multiple types of insults/diseases, such as stroke, traumatic brain injury, drug addiction and mood disorders. In this review, we will discuss what is known to date on these efforts and identify gaps in our knowledge regarding the link between M current and therapeutic potential for these disorders. We will outline the preclinical experiments that are yet to be performed to demonstrate the likelihood of success of this approach in human trials. Finally, we also address multiple pharmacological tools available to manipulate different K v 7 subunits and the relevant evidence for translational application in the clinical use for disorders of the central nervous system and multiple types of brain insults. We feel there to be great potential for manipulation of K v 7 channels as a novel therapeutic mode of intervention in the clinic, and that the paucity of existing therapies obligates us to perform further research, so that patients can soon benefit from such therapeutic approaches.

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Attenuating M‐current suppression in vivo by a mutant Kcnq2 gene knock‐in reduces seizure burden and prevents status epilepticus–induced neuronal death and epileptogenesis

Cited by 22 publications

References 35 publications

A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment

A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment

Functional responses of the hippocampus to hyperexcitability depend on directed, neuron‐specific KCNQ2 K⁺ channel plasticity

Pharmacological Manipulation of Kv7 Channels as a New Therapeutic Tool for Multiple Brain Disorders

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Attenuating M‐current suppression in vivo by a mutant Kcnq2 gene knock‐in reduces seizure burden and prevents status epilepticus–induced neuronal death and epileptogenesis

Cited by 22 publications

References 35 publications

A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment

A knock‐in mouse model for KCNQ2‐related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment

Functional responses of the hippocampus to hyperexcitability depend on directed, neuron‐specific KCNQ2 K+ channel plasticity

Pharmacological Manipulation of Kv7 Channels as a New Therapeutic Tool for Multiple Brain Disorders

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Functional responses of the hippocampus to hyperexcitability depend on directed, neuron‐specific KCNQ2 K⁺ channel plasticity