Evaluating whole genome sequence data from the Genetic Absence Epilepsy Rat from Strasbourg and its related non-epileptic strain

Casillas‐Espinosa, Pablo M.; Powell, Kim L.; Zhu, Mingyuan; Campbell, C. Ryan; Maia, Jessica M.; Ren, Zhong; Jones, Nigel C.; O’Brien, Terence J.; Petrovski, Steve

doi:10.1371/journal.pone.0179924

Cited by 21 publications

(14 citation statements)

References 42 publications

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“…mechanisms underlying ictogenesis and epileptogenesis by identifying novel genetic loci and profound changes in gene expression in humans and animal models [19][20][21][22][23][24]. However, the poor correlation between RNA expression and protein levels limits the value of isolated transcriptomic or genomic studies [25].…”

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confidence: 99%

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Pires

Leitner

Drummond

et al. 2020

Preprint

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Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioral disorders, and increased mortality from direct (e.g., Sudden Unexpected Death in Epilepsy [SUDEP], accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signaling networks associated with epilepsy, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry (MS) was performed on the hippocampal CA1-3 region, frontal cortex, and dentate gyrus microdissected from epilepsy and control cases (n=14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1-3 region, 296 proteins in the frontal cortex, and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signaling, and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein Subunit Beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signaling and G-protein–coupled receptors (GPCRs) in epilepsy. Our results provide insights into the molecular mechanisms underlying epilepsy, which may allow for novel targeted therapeutic strategies.

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confidence: 99%

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Pires

Leitner

Drummond

et al. 2020

Preprint

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“…The GAERS and NEC strains are both derived from the same original Wistar rat colony, but were selectively inbred to express, or not to express, absence seizures. 18,26 This then allowed us to investigate whether the genes that result in GGE in the GAERS strain (or the absence seizures themselves) can influence the incidence or severity of VPA-induced effects on the fetus. Interestingly, we did not note any marked differences in any of the consequences of gestational VPA exposure between these strains, suggesting that these factors do not play an important role.…”

Section: Discussionmentioning

confidence: 99%

“…We also used a variety of rat strains, including a strain with GGE-Genetic Absence Epilepsy Rats From Strasbourg (GAERS). 17 We also studied the genetically related Non-Epileptic Control (NEC) rat strain, 18 originating from the same Wistar colony but separated many decades ago, which does not manifest seizures. Outbred Wistar rats were also included to assess an unrelated nonepileptic strain.…”

Section: Introductionmentioning

confidence: 99%

A rat model of valproate teratogenicity from chronic oral treatment during pregnancy

et al. 2020

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Objective: Sodium valproate (VPA), the most effective antiepileptic drug for patients with genetic generalized epilepsy (GGE), is a potent human teratogen that increases the risk of a range of congenital malformations, including spina bifida. The mechanisms underlying this teratogenicity are not known, but may involve genetic risk factors. This study aimed to develop an animal model of VPA-induced birth defects. Methods: We used three different rat strains: inbred Genetic Absence Epilepsy Rats From Strasbourg (GAERS), a model of GGE with absence seizures; inbred Non-Epileptic Controls (NEC); and outbred nonepileptic Wistars. Female rats were fed standard chow or VPA (20 g/kg food) mixed in standard chow for 2 weeks prior to conception, and then mated with same-strain males. Treatment continued throughout pregnancy. Fetuses were extracted via C-section on gestational day 21 and examined for birth defects, including external assessment and spinal measurements. Results: VPA-exposed pups showed significant reductions in weight, length, and whole-body development compared with controls of all three strains (P < .0001).Gestational VPA treatment altered intravertebral distances, and resulted in underdeveloped vertebral arches between thoracic region T11 and caudal region C2 in most pups (GAERS, 100%; NEC, 95%; Wistar, 80%), more frequently than in controls (9%, 13%, 19%). Significance: Gestational VPA treatment results in similar developmental and morphological abnormalities in three rat strains, including one with GGE, indicating that the genetic underpinnings of epilepsy do not contribute markedly to VPA-induced birth defects. This model may be used in future studies to investigate mechanisms involved in the pathogenesis of antiepileptic drug-induced birth defects.

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“…Surgery was performed 6 weeks after SE or FPI, or at 6 months of age for the GAERS and WAG/Rij, as previously described . Briefly, animals were anesthetized with isoflurane.…”

Section: Methodsmentioning

confidence: 99%

A universal automated tool for reliable detection of seizures in rodent models of acquired and genetic epilepsy

Casillas‐Espinosa

Sargsyan²,

Melkonian³

et al. 2019

Epilepsia

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Summary Objective Prolonged electroencephalographic (EEG) monitoring in chronic epilepsy rodent models has become an important tool in preclinical drug development of new therapies, in particular those for antiepileptogenesis, disease modification, and treating drug‐resistant epilepsy. We have developed an easy‐to‐use, reliable, computational tool for automated detection of electrographic seizures from prolonged EEG recordings in rodent models of epilepsy. Methods We applied a novel method based on advanced time‐frequency analysis that detects EEG episodes with excessive activity in certain frequency bands. The method uses an innovative technique of short‐term spectral analysis, the Similar Basis Function algorithm. The method was applied for offline seizure detection from long‐term EEG recordings from four spontaneously seizing, chronic epilepsy rat models: the fluid percussion injury (n = 5 rats, n = 49 seizures) and post–status epilepticus models (n = 119 rats, n = 993 seizures) of acquired epilepsy, and two genetic models of absence epilepsy, Genetic Absence Epilepsy Rats from Strasbourg and Wistar Albino Glaxo from Rijswijk (n = 41 and 14 rats, n = 8733 and 825 seizures, respectively). Results Our comparative analysis revealed that the EEG amplitude spectra of these four rat models are remarkably similar during epileptiform activity and have a single expressed peak within the 17‐ to 25‐Hz frequency range. Focusing on this band, our computer program detected all seizures in the 179 rats. A quick semiautomated user inspection of the EEGs for the period of each identified event allowed quick rejection of artifact events. The overall processing time for 12‐day‐long recordings varied from a few minutes (5‐10) to 30 minutes, depending on the number of artifact events, which was strongly correlated with the signal quality of the raw EEG data. Significance Our automated seizure detection tool provides high sensitivity, with acceptable specificity, for long‐ and short‐term EEG recordings from both acquired and genetic chronic epilepsy rat models. This tool has the potential to improve the efficiency and rigor of preclinical research and therapy development using these models.

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Evaluating whole genome sequence data from the Genetic Absence Epilepsy Rat from Strasbourg and its related non-epileptic strain

Cited by 21 publications

References 42 publications

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

A rat model of valproate teratogenicity from chronic oral treatment during pregnancy

A universal automated tool for reliable detection of seizures in rodent models of acquired and genetic epilepsy

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