The developmental evolution of the seizure phenotype and cortical inhibition in mouse models of juvenile myoclonic epilepsy

Arain, Fazal Manzoor; Zhou, Chengwen; Ding, Li; Zaidi, Sahar; Gallagher, Martín J.

doi:10.1016/j.nbd.2015.05.016

Cited by 26 publications

(47 citation statements)

References 38 publications

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“…However, the myoclonic jerks were more frequent in the adolescent mice than in the adult mice, regardless of genotype, suggesting a possible role of age in the onset of myoclonic jerks. It has been noticed in epilepsy mouse models carrying Gabra1 mutations that myoclonic seizures are more prominent in older mice 25 . Regardless, there were more myoclonic jerks in the Gabrg2 +/Q390X mice in both adolescent and adult groups.…”

Section: Resultsmentioning

confidence: 99%

Heat induced temperature dysregulation and seizures in Dravet Syndrome/GEFS+ Gabrg2+/Q390X mice

et al. 2017

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It has been established that febrile seizures and its extended syndromes like generalized epilepsy with febrile seizures (FS) plus (GEFS+) and Dravet syndrome have been associated with mutations especially in SCN1A and GABRG2 genes. In patients, the onset of FS is likely due to the combined effect of temperature and inflammation in genetically vulnerable individuals because fever is often associated with infection. Much effort has been spent to understand the mechanisms underlying fever induction of seizures. In addition to the role of cytokines in FS, previous studies in Scn1a+/− knockout mice, a model of Dravet syndrome, indicated that temperature elevation alone could result in seizure generation, and the effect of elevated temperature inducing seizures was age-dependent. Here, we report the thermal effect in a different mouse model of Dravet syndrome, the Gabrg2+/Q390X knockin mouse. We demonstrated age-dependent dysregulated temperature control and that temperature elevation produced myoclonic jerks, generalized tonic clonic seizures (GTCSs) and heightened anxietylike symptoms in Gabrg2+/Q390X mice. The study indicated that regardless of other inflammatory factors, brief heat alone increased brain excitability and induced multiple types of seizures in Gabrg2+/Q390X mice, suggesting that mutations like GABRG2(Q390X) may alter brain thermal regulation and precipitate seizures during temperature elevations.

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Section: Resultsmentioning

confidence: 99%

Heat induced temperature dysregulation and seizures in Dravet Syndrome/GEFS+ Gabrg2+/Q390X mice

et al. 2017

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“…Mice were housed in a controlled facility with a 12 h light/dark schedule, a temperature and humidity controlled environment, and ad libitum water and food. We previously reported the construction of mice that heterozygously expressed the Gabra1(A322D) mutation in a congenic C57BL/6J background . Although wild‐type mice have very rare SWDs and polyspike complexes, we have previously shown that Gabra1 +/A322D and Gabra1 +/− mice have very frequent SWDs that are associated with behavior arrest and EMG attenuation and are inhibited by the anti‐absence seizure drug, ethosuximide .…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported the construction of mice that heterozygously expressed the Gabra1(A322D) mutation in a congenic C57BL/6J background . Although wild‐type mice have very rare SWDs and polyspike complexes, we have previously shown that Gabra1 +/A322D and Gabra1 +/− mice have very frequent SWDs that are associated with behavior arrest and EMG attenuation and are inhibited by the anti‐absence seizure drug, ethosuximide . In addition, in mutant, but not wild‐type mice, the polyspike discharges are often accompanied by myoclonic jerks and the SWDs …”

Section: Methodsmentioning

confidence: 99%

“…Recently, we developed a mouse model that expresses a human JME‐associated missense mutation (A322D) of the γ‐aminobutyric acid A (GABA A ) receptor α1 subunit. Early in life (postnatal day 35, P35), Gabra1 +/A322D mice have spontaneous absence seizures with SWDs, and, later in life (P120), they have spontaneous SWDs, myoclonic seizures, and a greater sensitivity to pentylenetetrazole (PTZ)–evoked myoclonic seizures than wild‐type mice . Therefore, the study of SWDs and myoclonic seizures in Gabra1 +/A322D mice will reveal the cerebral networks engaged in these two seizure types, results applicable to JME and, possibly, to other generalized epilepsy syndromes that confer also absence and myoclonic seizures.…”

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confidence: 99%

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Dynamics of sensorimotor cortex activation during absence and myoclonic seizures in a mouse model of juvenile myoclonic epilepsy

Ding

Gallagher

2016

Epilepsia

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Objective Generalized epilepsy syndromes often confer multiple types of seizures, but it is not known if these seizures activate separate or overlapping brain networks. Recently, we reported that mice with a juvenile myoclonic epilepsy mutation [Gabra1(A322D)] exhibited both absence and myoclonic generalized seizures. Here, we determined the time course of sensorimotor cortex activation and the spatial distribution of spike voltage during these two seizures. Methods We implanted Gabra1+/A322D mice with multiple EEG electrodes over bilateral somatosensory cortex barrel fields (S1) and anterior (aM1) and posterior (pM1) motor cortices and recorded absence seizures / spike-wave discharges (SWDs) and myoclonic seizures. We used nonlinear-association analyses and cross-correlation calculations to determine the strength, leading regions, and time delays of cortical coupling from the preictal to ictal states and within the spike and interspike periods. The distribution of spike voltage was also measured in SWDs and myoclonic seizures. Results EEG connectivity among all electrode pairs increased at the onset of both SWDs and myoclonic seizures. Surprisingly, during spikes of both seizure types, S1 led M1 with similar delay times. Myoclonic seizure spikes started more focally than SWD spikes with a significant majority appearing first only in S1 electrodes while a substantial fraction of SWD spikes were detected first in S1 and at least one M1 electrode. The absolute voltage of myoclonic seizure spikes was significantly higher than that of SWD spikes and there was a greater relative voltage over M1 during myoclonic seizure spikes than in the first one to two SWD spikes. Significance The leading sites in S1 and similar delay times suggest both SWDs and myoclonic seizures activate overlapping networks in sensorimotor cortex and thus, therapeutically targeting this network could potentially treat both seizures. Spike focality, absolute voltage and voltage distribution provide insight into neuronal activation during these two seizure types.

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“…Studies from mouse models indicate that deletion of GABRA1 is sufficient to cause absence epilepsy (Arain et al, 2012). The knockin mice carrying GABRA1(A322D) displayed absence and myoclonic jerks (Arain et al, 2015). The functional consequence of GABRA1 mutations that are associated with Dravet syndrome has not been characterized.…”

Section: Gabamentioning

confidence: 99%

Defects at the crossroads of GABAergic signaling in generalized genetic epilepsies

Kang

2017

Epilepsy Research

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Seizure disorders are very common and affect 3% of the general population. The recurrent unprovoked seizures that are also called epilepsies are highly diverse as to both underlying genetic basis and clinic presentations. Recent genetic advances and sequencing technologies indicate that many epilepsies previously thought to be without known causes, or idiopathic generalized epilepsies (IGEs), are virtually genetic epilepsy as they are caused by genetic variations. IGEs are estimated to account for ~15-20% of all epilepsies. Initially IGEs were primarily considered channelopathies, because the first genetic defects identified in IGEs involved ion channel genes. However, new findings indicate that mutations in many non ion channel genes are also involved in addition to those in ion channel genes. Interestingly, mutations in many genes associated with epilepsy affect GABAergic signaling, a major biological pathway in epilepsy. Additionally, many antiepileptic drugs work via enhancing GABAergic signaling. Hence, the review will focus on the mutations that impair GABAergic signaling and selectively discuss the newly identified STXBP1, PRRT2, and DNM1 in addition to those long-established epilepsy ion channel genes that also impair GABAergic signaling like SCN1A and GABAA receptor subunit genes. GABAergic signaling includes the pre- and post- synaptic mechanisms. Some mutations, such as STXBP1, PRRT2, DNM1, and SCN1A, impair GABAergic signaling mainly via pre-synaptic mechanisms while those mutations in GABAA receptor subunit genes impair GABAergic signaling via post-synaptic mechanisms. Nevertheless, these findings suggest impaired GABAergic signaling is a converging pathway of defects for many ion channel or non ion channel mutations associated with genetic epilepsies.

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The developmental evolution of the seizure phenotype and cortical inhibition in mouse models of juvenile myoclonic epilepsy

Cited by 26 publications

References 38 publications

Heat induced temperature dysregulation and seizures in Dravet Syndrome/GEFS+ Gabrg2+/Q390X mice

Heat induced temperature dysregulation and seizures in Dravet Syndrome/GEFS+ Gabrg2+/Q390X mice

Dynamics of sensorimotor cortex activation during absence and myoclonic seizures in a mouse model of juvenile myoclonic epilepsy

Defects at the crossroads of GABAergic signaling in generalized genetic epilepsies

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