Electrical Stimulation Seizure Models

Vliet, Erwin A. van; Gorter, Jan A.

doi:10.1016/b978-0-12-804066-9.00034-1

Cited by 2 publications

(4 citation statements)

References 94 publications

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“…In order to examine seizure sensitivity, we evaluated response of Kcnb1 G379R mice to the volatile chemoconvulsant flurothyl, a GABA A antagonist ( van Vliet et al, 2017 ). Latency to the first myoclonic jerk did not differ between genotypes, while latency to the first generalized tonic-clonic seizure (GTCS) with loss of posture was affected by genotype ( Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…We next investigated whether Kcnb1 G379R influenced latency to psychomotor seizures induced by long duration, low frequency stimulation (6 Hz, 3 s), a model of pharmacoresistant focal seizures ( van Vliet et al, 2017 ). Kcnb1 R /+ heterozygotes and WT littermates were subjected to 6 Hz stimulation and scored for the presence or absence of seizure activity (forelimb clonus, rearing, paddling or loss of posture).…”

Section: Resultsmentioning

confidence: 99%

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Epilepsy and neurobehavioral abnormalities in mice with a dominant-negative KCNB1 pathogenic variant

Hawkins

Misra

Jurado

et al. 2021

Neurobiology of Disease

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Developmental and epileptic encephalopathies (DEE) are a group of severe epilepsies that usually present with intractable seizures, developmental delay, and often have elevated risk for premature mortality. Numerous genes have been identified as a monogenic cause of DEE, including KCNB1 . The voltage-gated potassium channel K v 2.1, encoded by KCNB1 , is primarily responsible for delayed rectifier potassium currents that are important regulators of excitability in electrically excitable cells, including neurons. In addition to its canonical role as a voltage-gated potassium conductance, K v 2.1 also serves a highly conserved structural function organizing endoplasmic reticulum-plasma membrane junctions clustered in the soma and proximal dendrites of neurons. The de novo pathogenic variant KCNB1 -p.G379R was identified in an infant with epileptic spasms, and atonic, focal and tonic-clonic seizures that were refractory to treatment with standard antiepileptic drugs. Previous work demonstrated deficits in potassium conductance, but did not assess non-conducting functions. To determine if the G379R variant affected K v 2.1 clustering at endoplasmic reticulum-plasma membrane junctions, K v 2.1-G379R was expressed in HEK293T cells. K v 2.1-G379R expression did not induce formation of endoplasmic reticulum-plasma membrane junctions, and co-expression of K v 2.1-G379R with K v 2.1-wild-type lowered induction of these structures relative to K v 2.1-WT alone, consistent with a dominant negative effect. To model this variant in vivo, we introduced Kcnb1 G379R into mice using CRISPR/Cas9 genome editing. We characterized neuronal expression, neurological and neurobehavioral phenotypes of Kcnb1 G379R/+ ( Kcnb1 R/+ ) and Kcnb1 G379R/G379R ( Kcnb1 R/R ) mice. Immunohistochemistry studies on brains from Kcnb1 +/+ , Kcnb1 R/+ and Kcnb1 R/R mice revealed genotype-dependent differences in the expression levels of K v 2.1 protein, as well as associated K v 2.2 and AMIGO-1 proteins. Kcnb1 R/+ and Kcnb1 R/R mice displayed profound hyperactivity, repetitive behaviors, impulsivity and reduced anxiety. Spontaneous seizures were observed in Kcnb1 R/R mice, as well as seizures induced by exposure to novel environments and/ or handling. Both Kcnb1 R/+ and Kcnb1 R/R ...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Epilepsy and neurobehavioral abnormalities in mice with a dominant-negative KCNB1 pathogenic variant

Hawkins

Misra

Jurado

et al. 2021

Neurobiology of Disease

View full text Add to dashboard Cite

show abstract

“…We investigated whether the Kcnb1 G379R mutation influenced latency to seizures induced by the volatile chemoconvulsant flurothyl, a GABAA antagonist (van Vliet, 2017).…”

Section: Reduced Threshold For Induced Seizures In Kcnb1 G379r Micementioning

confidence: 99%

“…We next investigated whether the Kcnb1 mutation influenced latency to psychomotor seizures induced by long duration, low frequency stimulation (6 Hz, 3 sec), a model of pharmacoresistant focal seizures (van Vliet, 2017). Kcnb1 R/+ heterozygotes and WT littermates were subjected to 6 Hz stimulation and scored for the presence or absence of seizure activity (forelimb clonus, rearing, paddling or loss of posture).…”

Section: Reduced Threshold For Induced Seizures In Kcnb1 G379r Micementioning

confidence: 99%

Epilepsy and neurobehavioral abnormalities in mice with aKCNB1pathogenic variant that alters conducting and non-conducting functions of K_V2.1

Hawkins¹,

Misra

Jurado³

et al. 2019

Preprint

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Developmental and epileptic encephalopathies (DEE) are a group of severe epilepsies that usually present with intractable seizures, developmental delay and are at a higher risk for premature mortality. Numerous genes have been identified as a monogenic cause of DEE, including KCNB1. The voltage-gated potassium channel K V 2.1, encoded by KCNB1, is primarily responsible for delayed rectifier potassium currents that are important regulators of excitability in electrically excitable cells, including neurons and cardiomyocytes. The de novo pathogenic variant KCNB1-p.G379R was identified in an infant with epileptic spasms, atonic, focal and tonic-clonic seizures that were refractory to treatment with standard antiepileptic drugs. Previous work demonstrated deficits in potassium conductance, but did not assess non-conducting functions. To determine if the G379R variant affected clustering at endoplasmic reticulum-plasma membrane junctions K V 2.1-G379R was expressed in HEK293T cells. K V 2.1-G379R expression did not induce formation of endoplasmic reticulum-plasma membrane junctions, and coexpression of K V 2.1-G379R with K V 2.1-WT lowered induction of these structures relative to K V 2.1-WT alone, suggesting a dominant negative effect. To model this variant in vivo, we introduced Kcnb1 G379R into mice using CRISPR/Cas9 genome editing. We characterized neurological and neurobehavioral phenotypes of Kcnb1 G379R/+ (Kcnb1 R/+ ) and Kcnb1 G379R/G379R (Kcnb1 R/R ) mice, and screened for cardiac abnormalities. Immunohistochemistry studies on brains from Kcnb1 +/+ (WT), Kcnb1 R/+ and Kcnb1 R/R mice revealed genotype-dependent differences in the levels and subcellular localization of K V 2.1, with reduced plasma membrane expression of the K V 2.1-G379R protein, consistent with in vitro data. Kcnb1 R/+ and Kcnb1 R/R mice displayed profound hyperactivity, repetitive behaviors, impulsivity and reduced anxiety. In addition, both Kcnb1 R/+ and Kcnb1 R/R mice exhibited abnormal interictal EEG abnormalities, including isolated spike and slow waves. Spontaneous seizure events were observed in Kcnb1 R/R mice during exposure to novel environments and/or handling, while both Kcnb1 R/+ and Kcnb1 R/R mutants were more susceptible to induced seizures. Kcnb1 R/+ and Kcnb1 R/R mice exhibited prolonged rate-corrected QT interval on surface ECG recording. Overall, the Kcnb1 G379R mice recapitulate many features observed in individuals with DEE due to pathogenic variants in KCNB1. This new mouse model of KCNB1 associated DEE will be valuable for improving the understanding of the underlying pathophysiology and will provide a valuable tool for the development of therapies to treat this pharmacoresistant DEE.

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Electrical Stimulation Seizure Models

Cited by 2 publications

References 94 publications

Epilepsy and neurobehavioral abnormalities in mice with a dominant-negative KCNB1 pathogenic variant

Epilepsy and neurobehavioral abnormalities in mice with a dominant-negative KCNB1 pathogenic variant

Epilepsy and neurobehavioral abnormalities in mice with aKCNB1pathogenic variant that alters conducting and non-conducting functions of K_V2.1

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Electrical Stimulation Seizure Models

Cited by 2 publications

References 94 publications

Epilepsy and neurobehavioral abnormalities in mice with a dominant-negative KCNB1 pathogenic variant

Epilepsy and neurobehavioral abnormalities in mice with a dominant-negative KCNB1 pathogenic variant

Epilepsy and neurobehavioral abnormalities in mice with aKCNB1pathogenic variant that alters conducting and non-conducting functions of KV2.1

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Product

Resources

About

Epilepsy and neurobehavioral abnormalities in mice with aKCNB1pathogenic variant that alters conducting and non-conducting functions of K_V2.1