Defining the latent period of epileptogenesis and epileptogenic zone in a focal cortical dysplasia type II (FCDII) rat model

Kao, Hsin-Yi; Hu, Shuntong; Mihaylova, Temenuzhka; Ziobro, Julie; Ahn, EunSeon; Fine, Carli; Brang, David; Watson, Brendon O.; Wang, Yu

doi:10.1111/epi.16868

Cited by 11 publications

(7 citation statements)

References 52 publications

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“…Kao et al . 31 recently studied epileptogenesis in a rat model of Depdc5-related FCD type II, and documented a similar progression of immature electrographic patterns towards mature forms of cortical discharges. Using both intermittent and continuous EEG monitoring, they found that mature patterns gradually emerge from brief runs of SW complexes that progressively last longer, and finally morph into well-formed SWDs.…”

Section: Discussionmentioning

confidence: 93%

“…Using both intermittent and continuous EEG monitoring, they found that mature patterns gradually emerge from brief runs of SW complexes that progressively last longer, and finally morph into well-formed SWDs. 31 Likewise, in the GAERS rat model of absence-type epilepsy, epileptiform activity gradually progresses during epileptogenesis. Oscillatory epileptiform discharges emerge first, become progressively intermingled with SW complexes, and finally shape into fully mature SWDs.…”

Section: Discussionmentioning

confidence: 99%

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Early suppression of excitability in subcortical band heterotopia modifies epileptogenesis in rats

Hardy

Buhler

Suchkov

et al. 2022

Preprint

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Malformations of cortical development represent a major cause of epilepsy in childhood. However, the pathological substrate and dynamic changes leading to the development and progression of epilepsy remain unclear. Here, we characterized an etiology-relevant rat model of subcortical band heterotopia (SBH), a diffuse type of cortical malformation associated with drug-resistant seizures in humans. We used longitudinal electrographic recordings to monitor the age-dependent evolution of epileptiform discharges during the course of epileptogenesis in this model. We found both quantitative and qualitative age-related changes in seizures properties and patterns, accompanying a gradual progression towards a fully developed seizure pattern seen in adulthood. We also dissected the relative contribution of the band heterotopia and the overlying cortex to the development and age-dependent progression of epilepsy using timed and spatially targeted manipulation of neuronal excitability. We found that an early suppression of neuronal excitability in SBH slows down epileptogenesis in juvenile rats, whereas epileptogenesis is paradoxically exacerbated when excitability is suppressed in the overlying cortex. However, in rats with active epilepsy, similar manipulations of excitability have no effect on chronic spontaneous seizures. Together, our data support the notion that complex developmental alterations occurring in both the SBH and the overlying cortex concur to creating pathogenic circuits prone to generate seizures. Our study also suggests that early and targeted interventions could potentially influence the course of these altered developmental trajectories, and favorably modify epileptogenesis in malformations of cortical development.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Early suppression of excitability in subcortical band heterotopia modifies epileptogenesis in rats

Hardy

Buhler

Suchkov

et al. 2022

Preprint

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“…P16∼18 mice with three epidural screw electrodes were monitored for 8 h per day and then returned to the mother. Procedures for affixing electrodes in young rodents were performed as we previously described [8]. To detect the earliest seizures, a subset of <P14 mice were monitored for 3 h, two times every day, and then returned to the mother.…”

Section: Methodsmentioning

confidence: 99%

Perineuronal Nets Degradation and Parvalbumin Interneuron Loss in a Mouse Model of DEPDC5-Related Epilepsy

Yang¹,

Hu²,

Chang³

et al. 2022

Dev Neurosci

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DEPDC5, the key gene within the mechanistic target of rapamycin (mTOR) pathway, is one of the most common causative genes in patients with epilepsy and malformation of cortical development (MCD). Although somatic mutations in the dorsal cortical progenitors generate the malformed cortex, its pathogenesis of hyperexcitability is complex and remains unclear. We specifically deleted Depdc5 in the mouse forebrain dorsal progenitors to model DEPDC5-related epilepsy, and investigated whether and how parvalbumin interneurons were non-cell autonomously affected in the malformed cortex. We showed that long before seizures, coincident with microglia inflammation, proteolytic enzymes degraded perineuronal nets (PNN) in the malformed cortex, resulting in parvalbumin (PV+) interneuron loss and presynaptic inhibition impairment. Our studies therefore uncovered the hitherto unknown role of PNN in mTOR-related MCD, providing a new framework for mechanistic-based therapeutic development.

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“…CRISPR/Cas9 IUE manipulations via NHEJ and HDR are amenable to multiplexing—editing of multiple genes simultaneously (Chen et al., 2015; Mikuni et al., 2016). In addition to facilitating basic gene‐function studies, IUE‐mediated CRISPR/Cas9 genome editing has been used to model human diseases and assess specific patient variants such as loss‐of‐function variants in SPTAN1 seen in patients with early infantile epileptic encephalopathy type 5 (Hu et al., 2018; Kao et al., 2021; Lu et al., 2018; Ribierre et al., 2018; Wang et al., 2018). This is especially useful when modeling human disorders like FCD, with typified isolated regions of disorganized cortical neurons in an otherwise anatomically normal brain.…”

Section: Crispr/cas9 Genome Editing (Figure 2c)mentioning

confidence: 99%

“…This is especially useful when modeling human disorders like FCD, with typified isolated regions of disorganized cortical neurons in an otherwise anatomically normal brain. Whole brain transgenic mice do not recapitulate the isolated, clustered nature of dysplasia, but IUE of targeted regions of cortex does (Hu et al., 2018; Kao et al., 2021).…”

Section: Crispr/cas9 Genome Editing (Figure 2c)mentioning

confidence: 99%

Advances in inutero electroporation

Kittock

Pilaz

2023

Developmental Neurobiology

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In utero electroporation (IUE) is a technique developed in the early 2000s to transfect the neurons and neural progenitors of embryonic brains, thus enabling continued development in utero and subsequent analyses of neural development. Early IUE experiments focused on ectopic expression of plasmid DNA to analyze parameters such as neuron morphology and migration. Recent advances made in other fields, such as CRISPR/CAS9 genome editing, have been incorporated into IUE techniques as they were developed. Here, we provide a general review of the mechanics and techniques involved in IUE and explore the breadth of approaches that can be used in conjunction with IUE to study cortical development in a rodent model, with a focus on the novel advances in IUE techniques. We also highlight a few cases that exemplify the potential of IUE to study a broad range of questions in neural development.

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Defining the latent period of epileptogenesis and epileptogenic zone in a focal cortical dysplasia type II (FCDII) rat model

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 11 publications

References 52 publications

Early suppression of excitability in subcortical band heterotopia modifies epileptogenesis in rats

Early suppression of excitability in subcortical band heterotopia modifies epileptogenesis in rats

Perineuronal Nets Degradation and Parvalbumin Interneuron Loss in a Mouse Model of DEPDC5-Related Epilepsy

Advances in inutero electroporation

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