GABA is the principal inhibitory neurotransmitter in the CNS and acts via GABAA and GABAB receptors. Recently, a novel form of GABAA receptor-mediated inhibition, termed “tonic” inhibition, has been described. Whereas synaptic GABAA receptors underlie classical “phasic” GABAA receptor-mediated inhibition (inhibitory postsynaptic currents), tonic GABAA receptor-mediated inhibition results from the activation of extrasynaptic receptors by low concentrations of ambient GABA. Extrasynaptic GABAA receptors are composed of receptor subunits that convey biophysical properties ideally suited to the generation of persistent inhibition and are pharmacologically and functionally distinct from their synaptic counterparts. This book highlights ongoing work examining the properties of recombinant and native extrasynaptic GABAA receptors and their preferential targeting by endogenous and clinically relevant agents. In addition, it emphasizes the important role of extrasynaptic GABAA receptors in GABAergic inhibition throughout the CNS and identifies them as a major player in both physiological and pathophysiological processes.

1 Extrasynaptic GABA_A Receptors 1

Adam C. Errington

2 Extrasynaptic GABA_A Receptors: Subunit Composition, Distribution, and Regulation 15

Jean-Marc Fritschy and Patrizia Panzanelli

3 Biophysical Properties of Recombinant γ2- and δ-subunit Containing GABA_A Receptors 33

Robert L. Macdonald and Emmanuel J. Botzolakis

4 The Pharmacology of Extrasynaptic GABA_A Receptors 51

Keith A Wafford

5 Neurosteroids and Extrasynaptic GABA_A Receptors 75

William M. Connelly

6 Sources of GABA That Activate Extrasynaptic GABA_A Receptors 85

Damian Bright, Catriona Houston and Stephen Brickley

7 GPCR Modulation of Extrasynapitic GABA_A Receptors 125

William M. Connelly, Adam C. Errington, Josue G. Yague, Anna Cavaccini, Vincenzo Crunelli and Giuseppe Di Giovanni

8 Extrasynaptic GABAA Receptors and Tonic Inhibition in Spinal Cord 155

Emanuel Loeza-Alcocer, Carmen Andres, Justo Aguilar, Ricardo Felix and Rodolfo Delgado-Lezama

9 The Role of Peri-synaptic GABA Receptors After Stroke 179

Andrew N. Clarkson and Mary Chebib.

10 The Role of Extrasynaptic GABA_A Receptors in Focal Epilepsy 207

Matthew C. Walker and Ivan Pavlov

11 Gain-of-Function of Thalamic Extrasynaptic GABA-A Receptors in Typical Absence Seizures 223

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

12 GABAergic Control of the Hypothalamic-Pituitary-Adrenal (HPA) Axis: Role of Extrasynaptic GABA_A Receptors 239

Jamie Maguire

13 Tonic GABA_A-Receptor-Mediated Inhibition in Fragile-X Syndrome: A Cause of Dysfunction or a Pathway for a Cure? 271

Brandon S. Martin and Molly M. Huntsman

Index 285

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