Gain-of-function of thalamic extrasynaptic GABA-A receptors in typical absence seizures

Vincenzo Crunelli*, Giuseppe Di Giovanni, H. Rheinallt Parri, Adam C. Errington

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Epilepsy is generally viewed as resulting from an unbalanced excitatory/ inhibitory drive, where either excitatory transmission is enhanced and/or inhibitory transmission is decreased. However, studies in genetic and pharmacological models of non-convulsive typical absence seizures have revealed that an increased activation of extrasynaptic γ-aminobutyric acidA (GABAA) receptors (eGABAARs), and the resulting enhanced tonic GABAA inhibition in thalamocortical (TC) neurons, is a necessary and sufficient condition for the expression of these seizures. Importantly, in genetic absence models, the mechanism underlying eGABAAR gain of function is non-neuronal in nature as it results from a malfunction in the thalamic astrocytic GABA transporter, GAT-1. These results challenge the existing view that typical absence seizures are underpinned by a widespread loss of GABAergic function in TC circuits, and are supported by the evidence that drugs that increase GABAergic signalling elicit or aggravate absence seizures in animal model and humans. Furthermore, by highlighting a vital role for astrocytes and eGABAARs in the pathophysiology of typical absence epilepsy, these new findings offer novel targets for the development of more effective anti-absence drugs.

Original languageEnglish
Title of host publicationExtrasynaptic GABA A Receptors
EditorsA. Errington , G. Di Giovanni, V. Crunelli
PublisherSpringer
Pages223-237
Number of pages15
ISBN (Electronic)9781493914265
ISBN (Print)9781493914258
DOIs
Publication statusPublished - 23 Sep 2014

Publication series

NameThe Receptors
PublisherSpringer
Volume27

Fingerprint

Absence Epilepsy
GABA-A Receptors
Genetic Models
GABA Plasma Membrane Transport Proteins
Astrocytes
Pharmaceutical Preparations
Epilepsy
Seizures
Animal Models
Pharmacology
Neurons

Keywords

  • Cortex
  • Dopamine
  • GABA transporters
  • GABAB receptors
  • Serotonin
  • Thalamus
  • THIP

Cite this

Crunelli, V., Di Giovanni, G., Rheinallt Parri, H., & Errington, A. C. (2014). Gain-of-function of thalamic extrasynaptic GABA-A receptors in typical absence seizures. In A. Errington , G. Di Giovanni, & V. Crunelli (Eds.), Extrasynaptic GABA A Receptors (pp. 223-237). (The Receptors; Vol. 27). Springer. https://doi.org/10.1007/978-1-4939-1426-5_11
Crunelli, Vincenzo ; Di Giovanni, Giuseppe ; Rheinallt Parri, H. ; Errington, Adam C. / Gain-of-function of thalamic extrasynaptic GABA-A receptors in typical absence seizures. Extrasynaptic GABA A Receptors. editor / A. Errington ; G. Di Giovanni ; V. Crunelli. Springer, 2014. pp. 223-237 (The Receptors).
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abstract = "Epilepsy is generally viewed as resulting from an unbalanced excitatory/ inhibitory drive, where either excitatory transmission is enhanced and/or inhibitory transmission is decreased. However, studies in genetic and pharmacological models of non-convulsive typical absence seizures have revealed that an increased activation of extrasynaptic γ-aminobutyric acidA (GABAA) receptors (eGABAARs), and the resulting enhanced tonic GABAA inhibition in thalamocortical (TC) neurons, is a necessary and sufficient condition for the expression of these seizures. Importantly, in genetic absence models, the mechanism underlying eGABAAR gain of function is non-neuronal in nature as it results from a malfunction in the thalamic astrocytic GABA transporter, GAT-1. These results challenge the existing view that typical absence seizures are underpinned by a widespread loss of GABAergic function in TC circuits, and are supported by the evidence that drugs that increase GABAergic signalling elicit or aggravate absence seizures in animal model and humans. Furthermore, by highlighting a vital role for astrocytes and eGABAARs in the pathophysiology of typical absence epilepsy, these new findings offer novel targets for the development of more effective anti-absence drugs.",
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Crunelli, V, Di Giovanni, G, Rheinallt Parri, H & Errington, AC 2014, Gain-of-function of thalamic extrasynaptic GABA-A receptors in typical absence seizures. in A Errington , G Di Giovanni & V Crunelli (eds), Extrasynaptic GABA A Receptors. The Receptors, vol. 27, Springer, pp. 223-237. https://doi.org/10.1007/978-1-4939-1426-5_11

Gain-of-function of thalamic extrasynaptic GABA-A receptors in typical absence seizures. / Crunelli, Vincenzo; Di Giovanni, Giuseppe; Rheinallt Parri, H.; Errington, Adam C.

Extrasynaptic GABA A Receptors. ed. / A. Errington ; G. Di Giovanni; V. Crunelli. Springer, 2014. p. 223-237 (The Receptors; Vol. 27).

Research output: Chapter in Book/Report/Conference proceedingChapter

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T1 - Gain-of-function of thalamic extrasynaptic GABA-A receptors in typical absence seizures

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AU - Rheinallt Parri, H.

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PB - Springer

ER -

Crunelli V, Di Giovanni G, Rheinallt Parri H, Errington AC. Gain-of-function of thalamic extrasynaptic GABA-A receptors in typical absence seizures. In Errington A, Di Giovanni G, Crunelli V, editors, Extrasynaptic GABA A Receptors. Springer. 2014. p. 223-237. (The Receptors). https://doi.org/10.1007/978-1-4939-1426-5_11