Pharmacological profiles of generalized absence seizures in lethargic, stargazer and γ-hydroxybutyrate-treated model mice

Aizawa, Masahiro; Ito, Yoshihisa; Fukuda, Hideomi

doi:10.1016/s0168-0102(97)00066-7

Cited by 47 publications

(34 citation statements)

References 27 publications

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“…1 B). Taken together, the behavioral, electrographic, and pharmacological characters of seizures in ␣1A Ϫ/Ϫ mice are similar to those of mice absence seizures (Hosford et al, 1992;Aizawa et al, 1997).…”

Section: Absence Seizures With 3 Hz Swds In ␣1amentioning

confidence: 55%

“…Considering that both ␥2 and ␤4 are auxiliary subunits of ␣1 subunits, which have been known to modulate voltage dependence, kinetics, and amplitude of other types of Ca 2ϩ channels as well as the P/Q-type (Kang et al, 2001;Schjott et al, 2003), the residual SWDs in ␥2 stg/stg /␣lG Ϫ/Ϫ and ␤4 lh/lh /␣lG Ϫ/Ϫ mice appear independent of pathological interactions between ␣1A and dysfunctional ␥2 and ␤4 subunits. This concept is supported by pharmacological studies using these mice in which absence seizures in ␥2 stg/stg mice were sensitive to MK-801, which is ineffective in the treatment of absence seizures in other mice (Heller et al, 1983;Aizawa et al, 1997); however, a common thread that weaves through the generation and propagation of absence seizures in ␣1A Ϫ/Ϫ mice, as well as other mutant mice, is critical dependence on the ␣1G gene.…”

Section: Heterogeneity Of Absence Seizures: Is ␣1g a Common Mediator mentioning

confidence: 90%

“…Valproic acid (Sigma, St. Louis, MO) or ethoxusimide (Sigma) was diluted in physiological saline (0.85% NaCl) and injected intraperitoneally. The selection of the drug dose was based on published data (Heller et al, 1983;Aizawa et al, 1997) and preliminary experiments.…”

Section: Methodsmentioning

confidence: 99%

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Role of the α1G T-Type Calcium Channel in Spontaneous Absence Seizures in Mutant Mice

Song¹,

Kim²,

Choi³

et al. 2004

J. Neurosci.

134

108

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Alterations in thalamic T-type Ca2ϩ channels are thought to contribute to the pathogenesis of absence seizures. Here, we found that mice with a null mutation for the pore-forming ␣1A subunits of P/Q-type channels (␣1A Ϫ/Ϫ mice) were prone to absence seizures characterized by typical spike-and-wave discharges (SWDs) and behavioral arrests. Isolated thalamocortical relay (TC) neurons from these mice showed increased T-type Ca 2ϩ currents in vitro. To examine the role of increased T-currents in ␣1A Ϫ/Ϫ TC neurons, we cross-bred ␣1A Ϫ/Ϫ mice with mice harboring a null mutation for the gene encoding ␣1G, a major isotype of T-type Ca 2ϩ channels in TC neurons. ␣1AϪ/Ϫ /␣1G Ϫ/Ϫ mice showed a complete loss of T-type Ca 2ϩ currents in TC neurons and displayed no SWDs. Interestingly, ␣1AϪ/Ϫ / ␣1G ϩ/Ϫ mice had 75% of the T-type Ca 2ϩ currents in TC neurons observed in ␣1A ϩ/ϩ /␣1G ϩ/ϩ mice and showed SWD activity that was quantitatively similar to that in ␣1A Ϫ/Ϫ /␣1G ϩ/ϩ mice. Similar results were obtained using double-mutant mice harboring the ␣1G mutation plus another mutation also used as a model for absence seizures, i.e., lethargic (␤4 lh/lh ), tottering (␣1A tg/tg ), or stargazer (␥2 stg/stg ). The present results reveal that ␣1G T-type Ca 2ϩ channels play a critical role in the genesis of spontaneous absence seizures resulting from hypofunctioning P/Q-type channels, but that the augmentation of thalamic T-type Ca 2ϩ currents is not an essential step in the genesis of absence seizures.

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Section: Absence Seizures With 3 Hz Swds In ␣1amentioning

confidence: 55%

Section: Heterogeneity Of Absence Seizures: Is ␣1g a Common Mediator mentioning

confidence: 90%

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Role of the α1G T-Type Calcium Channel in Spontaneous Absence Seizures in Mutant Mice

Song¹,

Kim²,

Choi³

et al. 2004

J. Neurosci.

134

108

View full text Add to dashboard Cite

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“…The converse is also true: disruption of the Ca v 3.1 gene in mice leads to loss of thalamocortical T-currents and resistance to drug-induced absence seizures (Kim et al, 2001). Absence seizures in both human patients and animal models can be reduced by ethosuximide (Aizawa et al, 1997;Manning et al, 2004). Although other mechanisms of action have been proposed (Leresche et al, 1998), this drug is capable of blocking both native and recombinant T-channels at therapeutically relevant concentrations (Coulter et al, 1989;Gomora et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization and Neuronal Modeling of the Effects of Childhood Absence Epilepsy Variants ofCACNA1H, a T-Type Calcium Channel

Vitko¹,

Chen²,

Arias³

et al. 2005

J. Neurosci.

165

137

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Sequencing of the T-type Ca2ϩ channel gene CACNA1H revealed 12 nonsynonymous single nucleotide polymorphisms (SNPs) that were found only in childhood absence epilepsy (CAE) patients. One SNP, G773D, was found in two patients. The present study reports the finding of a third patient with this SNP, as well as analysis of their parents. Because of the role of T-channels in determining the intrinsic firing patterns of neurons involved in absence seizures, it was suggested that these SNPs might alter channel function. The goal of the present study was to test this hypothesis by introducing these polymorphisms into a human Ca v 3.2a cDNA and then study alterations in channel behavior using whole-cell patch-clamp recording. Eleven SNPs altered some aspect of channel gating. Computer simulations predict that seven of the SNPs would increase firing of neurons, with three of them inducing oscillations at similar frequencies, as observed during absence seizures. Three SNPs were predicted to decrease firing. Some CAE-specific SNPs (e.g., G773D) coexist with SNPs also found in controls (R788C); therefore, the effect of these polymorphisms were studied. The R788C SNP altered activity in a manner that would also lead to enhanced burst firing of neurons. The G773D-R788C combination displayed different behavior than either single SNP. Therefore, common polymorphisms can alter the effect of CAE-specific SNPs, highlighting the importance of sequence background. These results suggest that CACNA1H is a susceptibility gene that contributes to the development of polygenic disorders characterized by thalamocortical dysrhythmia, such as CAE.

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“…GHB is regarded as the best pharmacological model of typical absence seizures in animal models. [1][2][3][4] To our knowledge, there has not been a reported case of GHB-induced absence-like seizure in a human.…”

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confidence: 99%

γ-Hydroxybutyric Acid-Induced Electrographic Seizures

Cheung

Lucey

Duntley

et al. 2014

Journal of Clinical Sleep Medicine

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We describe a case of absence-like electrographic seizures during NREM sleep in a patient who was taking sodium oxybate, a sodium salt of γ-hydroxybutyric acid (GHB). An overnight full montage electroencephalography (EEG) study revealed numerous frontally predominant rhythmic 1.5-2 Hz sharp waves and spike-wave activity during stage N2 and N3 sleep at the peak dose time for sodium oxybate, resembling atypical absence-like electrographic seizures. The patient was later weaned off sodium oxybate, and a repeat study did not show any such electrographic seizures. Absence-like seizures induced by GHB had previously been described in experimental animal models. We present the fi rst reported human case of absence-like electrographic seizure associated with sodium oxybate. Keywords: seizure, narcolepsy, pharmacology Citation: Cheung J, Lucey BP, Duntley SP, Darken RS. γ-hydroxybutyric acid-induced electrographic seizures. J Clin Sleep Med 2014;10(7):811-812.http://dx.doi.org/10.5664/jcsm.3882 C A S E R E P O R T S γ -hydroxybutyric acid (GHB) is the active ingredient of sodium oxybate and is approved by the Food and Drug Administration for the treatment of cataplexy associated with narcolepsy. GHB and γ-butyrolactone, a prodrug of GHB, have been shown to reliably increase slow wave sleep as well as induce absence-like seizures accompanied by 3-6 Hz spikewave discharges (SWD) in monkeys and rats. GHB is regarded as the best pharmacological model of typical absence seizures in animal models.1-4 To our knowledge, there has not been a reported case of GHB-induced absence-like seizure in a human. REPORT OF CASEThe patient was a 35-year-old man who had narcolepsy with cataplexy as well as obstructive sleep apnea (OSA). He had been taking sodium oxybate for 2 years. The patient had no history of seizures, and his neurological examination was normal.A full-montage electroencephalography (EEG) polysomnography (PSG) was obtained, as the patient's wife reported abnormal sleep behaviors including somnambulism, sleep eating, somniloquy, and possible dream enactment. The patient took sodium oxybate 4.5 g with two separate doses for a total of 9 g on the night of the study as he would regularly at night. His PSG showed moderate-severe OSA with an apnea hypopnea index (AHI) of 29.4 respiratory events per hour of sleep. Additionally, the full-montage EEG revealed > 10 4-10 second runs of rhythmic frontally predominant 100-150 µV, 1.5-2 Hz sharp waves and spike-wave complexes during stage N2 and N3 sleep over a period of ~30 minutes (Figure 1). The EEG was otherwise unremarkable. On video review, no abnormal behavior was associated with the epileptiform activity. He was noted to have frequent somniloquy during REM and NREM, with large movements during REM, as well as REM without atonia meeting criteria for REM sleep behavior disorder. However, these episodes were not associated with the runs of spike-wave A brain magnetic resonance imaging (MRI) was later obtained and was normal. A routine daytime EEG including hyperventilation and phot...

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Pharmacological profiles of generalized absence seizures in lethargic, stargazer and γ-hydroxybutyrate-treated model mice

Cited by 47 publications

References 27 publications

Role of the α1G T-Type Calcium Channel in Spontaneous Absence Seizures in Mutant Mice

Role of the α1G T-Type Calcium Channel in Spontaneous Absence Seizures in Mutant Mice

Functional Characterization and Neuronal Modeling of the Effects of Childhood Absence Epilepsy Variants ofCACNA1H, a T-Type Calcium Channel

γ-Hydroxybutyric Acid-Induced Electrographic Seizures

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