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… 
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382 Citations

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.

Tonic GABAa current in absence epilepsy

One of the cellular thalamic pathologies that characterises absence seizures is an astrocyte-specific aberrant GAT-1 with the resulting elevated extracellular GABA level enhancing tonic GABAa current through two mechanisms: direct activation of high affinity e GABAARs and indirect increase in eGABAAR function due to activation of postsynaptic GABAbRs.

Augmentation of Tonic GABA A Inhibition in Absence Epilepsy : Therapeutic Value of Inverse Agonists at Extrasynaptic GABA A 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.

Targeting the GABAB Receptor for the Treatment of Epilepsy

Pre-clinical data in support of the efficacy of GABAB receptor agonists and antagonists in specific experimental models of seizures have not been translated into the clinical arena because of the potential for downstream adverse effects.

Transition to absence seizures and the role of GABAA receptors

Tonic Inhibition is Abolished in GABAA Receptor γ2R43Q Knock-in Mice with Absence Epilepsy and Febrile Seizures

It is suggested that an optimum level of tonic inhibition is required for normal thalamocortical function, such that deviations in either direction away from this optimum enhance susceptibility to absence seizures.

Neurological disorders: Inhibition: too much of a good thing?

  • K. Whalley
  • Biology, Psychology
    Nature Reviews Neuroscience
  • 2010
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.

GABAA receptor modulation by neurosteroids in models of temporal lobe epilepsies

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

Findings indicate that neuronal function in various brain regions are exacerbated with a gain or loss of function of tonic inhibition by GABA spillover, and receptor expression and factors for regulating the ambient GABA concentration are highlighted to gain a deeper understanding of pathology and therapeutic strategy for CNS diseases.

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.
...

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