Enhanced tonic GABAA inhibition in typical absence epilepsy

@article{Cope2009EnhancedTG,
  title={Enhanced tonic GABAA inhibition in typical absence epilepsy},
  author={David W. Cope and Giuseppe Di Giovanni and S. J. Fyson and Gergely Orban and Adam C. Errington and Magor L. Lőrincz and Timothy M. Gould and David A. Carter and Vincenzo Crunelli},
  journal={Nature medicine},
  year={2009},
  volume={15},
  pages={1392 - 1398}
}
The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired γ-aminobutyric acid (GABA)-ergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA receptor–dependent 'tonic' inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake… 

Augmentation of Tonic GABAA Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABAA Receptors

The results challenge the existing theory that typical absence seizures are underpinned by a widespread loss of GABAergic function in thalamocortical circuits and illustrate a vital role for astrocytes in the pathology of typical absence epilepsy.

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The results challenge the existing theory that typical absence seizures are underpinned by a widespread loss of GABAergic function in thalamocortical circuits and illustrate a vital role for astrocytes in the pathology of typical absence epilepsy.

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It is found that treating rat brain slices with two drugs that cause seizures in animal models significantly increased the amplitude of tonic GABAAR currents in thalamocortical neurons, suggesting enhanced, rather than reduced, tonic inhibition is a common cause of seizures in several animal models of absence epilepsy.

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Surprisingly, the level of tonic inhibition in DGGCs remains unchanged, consistent with the idea that it becomes mediated by GABAARs containing other subunits, and in parallel, tonic inhibited in a TLE model ceases to be sensitive to neurosteroid potentiation, as predicted by the anatomic plasticity.

Pathophysiological power of improper tonic GABAA conductances in mature and immature models

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Cortical Tonic Inhibition Regulates the Expression of Spike-and-Wave Discharges Associated with Absence Epilepsy

An optimum level of tonic inhibition in the thalamocortical circuit is required for normal functioning and that a deviation from this optimum results in aberrant thalamic inhibitory tonic function, SWDs and absence seizures.
...

References

SHOWING 1-10 OF 94 REFERENCES

Evidence for GABAB-mediated mechanisms in experimental generalized absence seizures.

  • O. Snead
  • Biology, Psychology
    European journal of pharmacology
  • 1992

Downregulation of tonic GABA currents following epileptogenic stimulation of rat hippocampal cultures

The results reveal a novel form of neural plasticity, that epileptogenic stimulation can selectively downregulate extrasynaptic GABAA receptors while leaving synaptic GabAA receptors unchanged, and suggest that regulation of tonic inhibition may also play an important role during epileptogenesis.

Hippocampal GABA transporter function in temporal-lobe epilepsy

In amygdala-kindled rats, a model for human epilepsy, a decrease in glutamate-induced GABA release was associated with a 48% decrease in the number of GABA transporters, and this data suggest that temporal-lobe epilepsy is characterized in part by a loss of glutamate-stimulated GABA release that is secondary to a reduction in theNumber of GABAtransporters.

Reduced cortical inhibition in a mouse model of familial childhood absence epilepsy

A mouse model harboring a γ2 subunit point mutation (R43Q) found in a large Australian family demonstrated behavioral arrest associated with 6-to 7-Hz spike-and-wave discharges, which are blocked by ethosuximide, a first-line treatment for absence epilepsy in man.

GABAA Receptor γ2 Subunit Mutations Linked to Human Epileptic Syndromes Differentially Affect Phasic and Tonic Inhibition

The data suggests that the phenotypic specificity of mutations affecting the GABAA receptor γ2 gene may result from different actions specific to distinct modes of GABAergic signaling, at least in part by reducing surface expression of the α5 subunit.

Mutant GABAA receptor γ2-subunit in childhood absence epilepsy and febrile seizures

It is found that the mutation in GABRG2 (encoding the γ2-subunit) abolished in vitro sensitivity to diazepam, raising the possibility that endozepines do in fact exist and have a physiological role in preventing seizures.

Trafficking of GABAA Receptors, Loss of Inhibition, and a Mechanism for Pharmacoresistance in Status Epilepticus

GA exposure mimics the effects of SE on mIPSC and tonic GABAA current amplitudes in granule cells, consistent with the model predictions, and provides a potential mechanism for the inhibitory loss that characterizes initiation of SE and for the pharmacoresistance to benzodiazepines.

Multiple and Plastic Receptors Mediate Tonic GABAA Receptor Currents in the Hippocampus

It is shown that α5GABAARs contribute to tonic currents in pyramidal cells only when ambient GABA concentrations increase (as may occur during increased brain activity), and multiple components of tonic GABAA receptor-mediated conductance that are activated by low GABA concentrations are revealed.

Deep Layer Somatosensory Cortical Neurons Initiate Spike-and-Wave Discharges in a Genetic Model of Absence Seizures

It is shown that absence seizures in Genetic Absence Epilepsy Rats from Strasbourg, a well established genetic model of this disease, arise from the facial somatosensory cortex, and it is found that epileptic discharges are initiated in layer 5/6 neurons of this cortical region.
...