A Critical Evaluation of the Gamma‐Hydroxybutyrate (<scp>GHB</scp>) Model of Absence Seizures

Venzi, Marcello; Giovanni, Giuseppe Di; Crunelli, Vincenzo

doi:10.1111/cns.12337

Cited by 32 publications

(39 citation statements)

References 148 publications

(285 reference statements)

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“…It should be stated that selective genetic deletion of Ca V 3.2 and Ca V 3.3 channels in mouse TRN neurons abolishes burst‐firing and has little effect on, or even exacerbates, pharmacological absence seizures generated by systemic administration of γ‐butyrolactone (GBL) . We note, however that the GBL model does not induce typical absence seizures in mice . Rather than displaying SWDs, the hallmark of absence seizures, mice injected with GBL and the neuroactive drug into which it is converted (γ‐hydroxybutyric acid; GHB) demonstrate slow oscillating waves, lacking spikes and that are more comparable to a hypnotic state.…”

Section: Discussionmentioning

confidence: 90%

“…39 We note, however that the GBL model does not induce typical absence seizures in mice. 40 Rather than displaying SWDs, the hallmark of absence seizures, mice injected with GBL and the neuroactive drug into which it is converted (c-hydroxybutyric acid; GHB) demonstrate slow oscillating waves, lacking spikes and that are more comparable to a hypnotic state. Furthermore, GHB is a known c-aminobutyric acid (GABA) agonist and mimics the native contribution of the GABAergic TRN neurons by hyperpolarizing thalamocortical neurons, thus a functional TRN is intrinsically redundant in this pharmacological model.…”

Section: Altered Ca V 32 Activity As a Trigger For Epileptic Seizuresmentioning

confidence: 99%

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Ca_V3.2 drives sustained burst‐firing, which is critical for absence seizure propagation in reticular thalamic neurons

et al. 2018

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SummaryObjectiveGenetic alterations have been identified in the CACNA1H gene, encoding the CaV3.2 T‐type calcium channel in patients with absence epilepsy, yet the precise mechanisms relating to seizure propagation and spike‐wave‐discharge (SWD) pacemaking remain unknown. Neurons of the thalamic reticular nucleus (TRN) express high levels of CaV3.2 calcium channels, and we investigated whether a gain‐of‐function mutation in the Cacna1h gene in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) contributes to seizure propagation and pacemaking in the TRN.MethodsPathophysiological contributions of CaV3.2 calcium channels to burst firing and absence seizures were assessed in vitro using acute brain slice electrophysiology and quantitative real‐time polymerase chain reaction (PCR) and in vivo using free‐moving electrocorticography recordings.Results TRN neurons from GAERS display sustained oscillatory burst‐firing that is both age‐ and frequency‐dependent, occurring only in the frequencies overlapping with GAERS SWDs and correlating with the expression of a CaV3.2 mutation‐sensitive splice variant. In vivo knock‐down of CaV3.2 using direct thalamic injection of lipid nanoparticles containing CaV3.2 dicer small interfering (Dsi) RNA normalized TRN burst‐firing, and in free‐moving GAERS significantly shortened seizures.SignificanceThis supports a role for TRN CaV3.2 T‐type channels in propagating thalamocortical network seizures and setting the pacemaking frequency of SWDs.

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Section: Discussionmentioning

confidence: 90%

Section: Altered Ca V 32 Activity As a Trigger For Epileptic Seizuresmentioning

confidence: 99%

Ca_V3.2 drives sustained burst‐firing, which is critical for absence seizure propagation in reticular thalamic neurons

et al. 2018

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“…Behavioral symptoms such as muscle twitching were most prominent during the bursting stage of PDs (see also Venzi et al, 2015), and motor symptoms commonly accompanied atypical absence seizures. The continuous stage of GBL-induced PDs was mainly associated with immobility and diminished response to sensory stimuli; the prolonged duration of PDs, often mixed with low-frequency (< 2-Hz) activity, suggested absence status epilepticus.…”

Section: Discussionmentioning

confidence: 99%

“…A commonly used acute model that reflects clinical and pharmacological characteristics of human absence seizures is the gamma-hydroxybutyric acid (GHB) rat model (Snead, 1988;Snead et al, 1999;Venzi et al, 2015). When GHB is administered, rats experience an arrest of motor activity, staring and occasional twitching of the vibrissae and facial muscles, concomitant with 4 to 6 Hz paroxysmal discharges (PDs) 1 in the EEG.…”

Section: Introductionmentioning

confidence: 99%

The hippocampus participates in a pharmacological rat model of absence seizures

Arcaro

Chu

et al. 2016

Epilepsy Research

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SUMMARYObjective-Using the gamma-butyrolactone (GBL) model of absence seizures in Long-Evans rats, this study investigated if 2.5-6 Hz paroxysmal discharges (PDs) induced by GBL were synchronized among the thalamocortical system and the hippocampus, and whether inactivation of the hippocampus affected PDs.Methods-Local field potentials were recorded by chronically implanted depth electrodes in the neocortex (frontal, parietal, visual), ventrolateral thalamus and dorsal hippocampal CA1 area. In separate experiments, multiple unit recordings were made at the hippocampal CA1 pyramidal cell layer, or the mid-septotemporal hippocampus was inactivated by local infusion of GABA A receptor agonist muscimol.Results-As PDs developed following GBL injection, coherence of local field potentials at 2.5-6 Hz increased between the hippocampus and thalamus, and between the hippocampus and the neocortex. Hippocampal theta rhythm was disrupted when GBL induced immobility in the rats. The probability of hippocampal multiple unit firing significantly increased at 40 -80 ms prior to the negative peak of thalamic PDs. Coherence between hippocampal multiple unit activity and thalamic field potentials at 2.5-6 Hz was significantly increased after GBL injection. Muscimol infusion to inactivate the mid-septotemporal hippocampus, as compared to saline infusion, significantly decreased the peak frequency of the PDs induced by GBL, decreased 30-120 Hz hippocampal gamma power, and hastened the transition of PDs to 1-2 Hz slow waves.Significance-During GBL induced 2.5-6 Hz PDs, a hallmark of absence seizure, increased synchronization between the hippocampus and the thalamocortical network was indicated by frequency and temporal correlation analysis. These results suggest that the hippocampus was entrained by thalamocortical activity in the present model of absence seizures. Prolonged synchronization of the hippocampus may result in synaptic alterations that may explain the

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“…33 Typically these are characterized by bilaterally synchronous spike-wave discharges that entrain thalamocortical circuitry, and are associated with behavioral arrest. These GABA B R agonist-induced absence-like seizures are blocked by ethosuximide and by GABA B R antagonists.…”

Section: Discussionmentioning

confidence: 99%

The GIRK2 subunit is involved in IS‐like seizures induced by GABA_B receptor agonists

et al. 2015

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Monica Blichowski is a second year medical student at the University of Toronto. SUMMARYObjective: Infantile spasms (or IS) is a catastrophic childhood epilepsy that is particularly prevalent in children with Down syndrome. Previously, we have shown that the Ts65Dn (Ts) mouse model of Down syndrome is a useful substrate upon which to develop an animal model of infantile spasms. Specifically, the Ts mouse is exquisitely sensitive to the electroencephalography (EEG) and behavioral effects of c-aminobutyric acid (GABA) B receptor (GABA B R) agonists with a resultant phenotype that bears behavioral, EEG, and pharmacologic semblance to infantile spasms in humans. The G protein-coupled inward rectifying potassium channel subunit 2 (GIRK2) gene, KCNJ6, is overexpressed in Ts mice, and the GABA B Rmediated GIRK2 current is significantly increased in these mutant animals as well. Therefore, we formulated the hypothesis that the GIRK2 channel plays a significant role in the behavioral (measured by acute extensor spasms quantification) and EEG (measured by the electrodecremental response duration) phenotype induced in the Ts mice by GABA B R agonists. Methods: GIRK2À/À , +/À , and +/+ mice were treated with c-butyrolactone (GBL), a prodrug of the GABA B R agonist c-hydroxybutyric acid, and the specific GABA B R agonist baclofen (BAC) under continuous EEG monitoring. These drugs induce epileptiform bursts, extensor spasms, and an electrodecremental response (EDR) in Ts mice at low doses, and in wild-type mice at high doses. A dose-response curve was ascertained with two treatment groups: GBL (100, 200, and 400 mg/kg) and BAC (4,8,12, and 16 mg/ kg). We determined the baseline, the presence and duration of electrodecremental epochs (EDEs), and quantified acute epileptic extensor spasms. Results: Analysis of EEG and behavior of GIRK2 À/À , +/À , and +/+ mice after treatment with GABA B R agonists and antagonists, indicate that GIRK2 À/À mice are highly resistant to GABA B R agonist-induced EEG and behavioral changes. Significance: These data increase the possibility that GIRK2 channel function plays a major role in the genesis of infantile spasms.

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A Critical Evaluation of the Gamma‐Hydroxybutyrate (GHB) Model of Absence Seizures

Cited by 32 publications

References 148 publications

Ca_V3.2 drives sustained burst‐firing, which is critical for absence seizure propagation in reticular thalamic neurons

Ca_V3.2 drives sustained burst‐firing, which is critical for absence seizure propagation in reticular thalamic neurons

The hippocampus participates in a pharmacological rat model of absence seizures

The GIRK2 subunit is involved in IS‐like seizures induced by GABA_B receptor agonists

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A Critical Evaluation of the Gamma‐Hydroxybutyrate (GHB) Model of Absence Seizures

Cited by 32 publications

References 148 publications

CaV3.2 drives sustained burst‐firing, which is critical for absence seizure propagation in reticular thalamic neurons

CaV3.2 drives sustained burst‐firing, which is critical for absence seizure propagation in reticular thalamic neurons

The hippocampus participates in a pharmacological rat model of absence seizures

The GIRK2 subunit is involved in IS‐like seizures induced by GABAB receptor agonists

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Product

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Ca_V3.2 drives sustained burst‐firing, which is critical for absence seizure propagation in reticular thalamic neurons

Ca_V3.2 drives sustained burst‐firing, which is critical for absence seizure propagation in reticular thalamic neurons

The GIRK2 subunit is involved in IS‐like seizures induced by GABA_B receptor agonists