Effects of the T-type calcium channel CaV3.2 R1584P mutation on absence seizure susceptibility in GAERS and NEC congenic rats models

Casillas‐Espinosa, Pablo M.; Lin, Runxuan; Li, Rui; Nandakumar, Nanda; Dawson, G M; Braine, Emma L.; Martin, Benoı̂t; Powell, Kim L.; O’Brien, Terence J.

doi:10.1016/j.nbd.2023.106217

Cited by 5 publications

(2 citation statements)

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“…Absence seizures, a pathognomonic seizure type of IGE, appear in humans during early childhood and are characterized by spike–wave discharges (SWDs) on the accompanying electroencephalogram (EEG). GAERS gradually develop seizures as they mature, starting to displaying SWDs in epidural recordings at approximately 4–6 weeks of age; the seizures continue to increase in frequency and duration until adulthood (4–6 months of age) 1,2 . In contrast, nonepileptic control rats (NEC) were derived from the same original Wistar strains as GAERS but selectively inbred not to express seizures at any age 1 …”

Section: Introductionmentioning

confidence: 99%

Transmembrane α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor regulatory protein expression during the development of absence seizures in genetic absence epilepsy rats from Strasbourg

Casillas‐Espinosa,

Lin,

et al. 2023

Epilepsia

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The transmembrane α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) regulatory proteins (TARPs), γ2 (stargazin), γ3, γ4, γ5, γ7, and γ8, are a family of proteins that regulate AMPAR trafficking, expression, and biophysical properties that could have a role in the development of absence seizures. Here, we evaluated the expression of TARPs and AMPARs across the development of epilepsy in the genetic absence epilepsy rats from Strasbourg (GAERS) model of idiopathic generalized epilepsy (IGE) with absence seizures. Pre‐epileptic (7‐day‐old), early epileptic (6‐week‐old), and chronically epileptic (16‐week‐old) GAERS, and age‐matched male nonepileptic control rats (NEC) were used. Electroencephalographic (EEG) recordings were acquired from the 6‐ and 16‐week‐old animals to quantify seizure expression. Somatosensory cortex (SCx) and whole thalamus were collected from all the animals to evaluate TARP and AMPAR mRNA expression. Analysis of the EEG demonstrated a gradual increase in the number and duration of seizures across GAERS development. mRNA expression of the TARPs γ2, γ3, γ4, γ5, and γ8 in the SCx, and γ4 and γ5 in the thalamus, increased as the seizures started and progressed in the GAERS compared to NEC. There was a temporal association between increased TARP expression and seizures in GAERS, highlighting TARPs as potential targets for developing novel treatments for IGE with absence seizures.

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Section: Introductionmentioning

confidence: 99%

Transmembrane α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor regulatory protein expression during the development of absence seizures in genetic absence epilepsy rats from Strasbourg

Casillas‐Espinosa,

Lin,

et al. 2023

Epilepsia

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“…Additionally, GAERS manifest anxiety and depressive-like behavior, cross-modal recognition memory, which represent neuropsychiatric comorbidities commonly present in the human condition. [21][22][23] Furthermore, studies over the past few decades have revealed that GAERS seizures have a similar ASM therapy response to those individuals suffering from absence epilepsy.…”

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Diurnal circadian clock gene expression is altered in models of genetic and acquired epilepsy

Yamakawa,

Patel,

Lin

et al. 2023

Epilepsia Open

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ObjectivesGrowing evidence demonstrates a relationship between epilepsy and the circadian system. However, relatively little is known about circadian function in disease states, such as epilepsy. This study aimed to characterize brain and peripheral core circadian clock gene expression in rat models of genetic and acquired epilepsy.MethodsFor the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) study we used 40 GAERS and 40 non‐epileptic control (NEC) rats. For the kainic acid status epilepticus (KASE) study, we used 40 KASE and 40 sham rats. Rats were housed in a 7am:7pm light‐dark cycle. Hypothalamus, hippocampus, liver, and small intestine samples were collected every 3 hours throughout the light period. We then assessed core diurnal clock gene expression of per1, cry1, clock and bmal1.ResultsIn the GAERS rats, all tissues exhibited significant changes in clock gene expression (p<0.05) when compared to NEC. In the KASE rats, there were fewer effects of the epileptic condition in the hypothalamus, hippocampus, or small intestine (p>0.05) compared to shams.SignificanceThese results indicate marked diurnal disruption to core circadian clock gene expression in rats with both generalized and focal chronic epilepsy. This could contribute to epileptic symptomology and implicate the circadian system as a viable target for future treatments.

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Huperzine A suppresses absence seizures in the genetic absence epilepsy rat from Strasbourg (GAERS) model of genetic generalized epilepsy with absence seizures

Casillas‐Espinosa,

Garcia‐Olivares,

et al. 2024

Epilepsia Open

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ObjectiveWe evaluated huperzine A treatment in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) model of genetic generalized epilepsy (GGE) with absence seizures.MethodsAdult male GAERS (N = 15) were implanted with EEG recording electrodes 10 days before receiving study drug. Each animal received the following six treatments as a single, intraperitoneal dose, 7 days apart (in random order): huperzine A (0.3, 1.0, or 3.0 mg/kg), two periods of vehicle (0.9% NaCl), or ethosuximide (100 mg/kg) as a positive control. Electroencephalograms (EEGs) were acquired for 24 h before and after each treatment and analyzed for seizure activity during the 90‐min period immediately post‐treatment, including 30‐min intervals at 30, 60, and 90 min. Additional analyses evaluated seizure activity over the 24‐h post‐treatment period using 60‐min intervals at 6, 12, and 24 h. The cumulative 24‐h periods before and after each administered treatment were also compared.ResultsTwo‐way ANOVA showed a treatment difference [F(91,182) = 3.592, p < 0.0001] on the number of seizures over the first 90‐min post‐treatment (primary outcome); Tukey's post hoc analyses showed that, compared to vehicle, huperzine A (3.0 mg/kg) significantly reduced seizures in the 30‐min (p = 0.02) and 60‐min (p = 0.001) intervals, and ethosuximide significantly reduced seizures at all measured time intervals except the 1‐h blocks at 12 and 24 h. Huperzine A 3.0 mg/kg and ethosuximide significantly reduced seizures during the cumulative 24‐h post‐treatment period relative to pretreatment baseline. While huperzine A 3.0 mg/kg did not differ significantly from ethosuximide at any time point, the study was not designed to evaluate non‐inferiority. The only adverse event after huperzine A or ethosuximide was mild, dose‐dependent sedation.SignificanceHuperzine A potently suppressed absence‐like seizures in GAERS, albeit with a shorter duration of action relative to ethosuximide, showing promise for clinical efficacy in GGE.Plain Language SummaryThis study looked at how huperzine A affects seizures in rats with similar abnormal brain activity as seen in humans with absence epilepsy. Rats received different treatments, placebo (i.e., saline solution), huperzine A, and ethosuximide. Ethosuximide is considered a gold standard treatment for absence epilepsy. We recorded brain activity to measure seizures before and after each treatment. We found that huperzine A (3.0 mg/kg) reduced seizures soon after treatment, like ethosuximide. Both treatments appeared safe, causing only mild sleepiness. The study shows that huperzine A could be a good new treatment for a type of absence epilepsy.

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Effects of the T-type calcium channel CaV3.2 R1584P mutation on absence seizure susceptibility in GAERS and NEC congenic rats models

Cited by 5 publications

References 90 publications

Transmembrane α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor regulatory protein expression during the development of absence seizures in genetic absence epilepsy rats from Strasbourg

Transmembrane α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor regulatory protein expression during the development of absence seizures in genetic absence epilepsy rats from Strasbourg

Diurnal circadian clock gene expression is altered in models of genetic and acquired epilepsy

Huperzine A suppresses absence seizures in the genetic absence epilepsy rat from Strasbourg (GAERS) model of genetic generalized epilepsy with absence seizures

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