HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 95/5/2796    most recent 01122.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (22) Citing Articles via Google Scholar Google Scholar Articles by Glykys, J. Articles by Mody, I. Search for Related Content PubMed PubMed Citation Articles by Glykys, J. Articles by Mody, I.

Hippocampal Network Hyperactivity After Selective Reduction of Tonic Inhibition in GABA_A Receptor 5 Subunit–Deficient Mice

Interdepartmental PhD Program for Neuroscience and Departments of Neurology and Physiology, David Geffen School of Medicine at the University of California, Los Angeles, California

Submitted 24 October 2005; accepted in final form 30 January 2006

Functionally, -aminobutyric acid receptor (GABAR)–mediated inhibition can be classified as phasic (synaptic) and tonic (extrasynaptic). The GABARs underlying tonic inhibition assemble from subunits different from those responsible for phasic inhibition. We wanted to assess the excitability of hippocampal pyramidal cell (PC) networks following a selective impairment of tonic inhibition. This is difficult to accomplish by pharmacological means. Because the GABAR 5 subunits mostly mediate the tonic inhibition in CA1 and CA3 PCs, we quantified changes in tonic inhibition and examined network excitability in slices of adult gabra5^–/– mice. In gabra5^–/– CA1 and CA3 PCs tonic inhibitory currents were 60 and 53%, respectively, of those recorded in wild type (WT), with no alterations in phasic inhibition. The amount of tonic inhibition recorded in slices was significantly affected by the method of slice storage (interface or submerged chamber). Field recordings in gabra5^–/– CA3 pyramidal layer showed an increased network excitability that was decreased by the GABAR agonist muscimol at a concentration that restored the tonic inhibition of gabra5^–/– PCs to the WT level without altering phasic inhibition. Through a battery of pharmacological experiments, we have identified subunit–containing GABARs as the mediators of the residual tonic inhibition in gabra5^–/– PCs. Our study is consistent with an important role of tonic inhibition in the control of hippocampal network excitability and highlights selective enhancers of tonic inhibition as promising therapeutic approaches for diseases involving network hyperexcitability.

This article has been cited by other articles:

				G. Curia, T. Papouin, P. Seguela, and M. Avoli Downregulation of Tonic GABAergic Inhibition in a Mouse Model of Fragile X Syndrome Cereb Cortex, September 11, 2008; (2008) bhn159v1. [Abstract] [Full Text] [PDF]

				B. K. Andrasfalvy, J. K. Makara, D. Johnston, and J. C. Magee Altered synaptic and non-synaptic properties of CA1 pyramidal neurons in Kv4.2 knockout mice J. Physiol., August 15, 2008; 586(16): 3881 - 3892. [Abstract] [Full Text] [PDF]

				J. Glykys, E. O. Mann, and I. Mody Which GABAA Receptor Subunits Are Necessary for Tonic Inhibition in the Hippocampus? J. Neurosci., February 6, 2008; 28(6): 1421 - 1426. [Abstract] [Full Text] [PDF]

				E. Eugene, C. Depienne, S. Baulac, M. Baulac, J. M. Fritschy, E. Le Guern, R. Miles, and J. C. Poncer GABAA Receptor {gamma}2 Subunit Mutations Linked to Human Epileptic Syndromes Differentially Affect Phasic and Tonic Inhibition J. Neurosci., December 19, 2007; 27(51): 14108 - 14116. [Abstract] [Full Text] [PDF]

				R. P. Bonin, L. J. Martin, J. F. MacDonald, and B. A. Orser {alpha}5GABAA Receptors Regulate the Intrinsic Excitability of Mouse Hippocampal Pyramidal Neurons J Neurophysiol, October 1, 2007; 98(4): 2244 - 2254. [Abstract] [Full Text] [PDF]

				J. Szabadics, G. Tamas, and I. Soltesz Different transmitter transients underlie presynaptic cell type specificity of GABAA,slow and GABAA,fast PNAS, September 11, 2007; 104(37): 14831 - 14836. [Abstract] [Full Text] [PDF]

				J. A. Gray and B. L. Roth Molecular Targets for Treating Cognitive Dysfunction in Schizophrenia Schizophr Bull, September 1, 2007; 33(5): 1100 - 1119. [Abstract] [Full Text] [PDF]

				J. Glykys and I. Mody The main source of ambient GABA responsible for tonic inhibition in the mouse hippocampus J. Physiol., August 1, 2007; 582(3): 1163 - 1178. [Abstract] [Full Text] [PDF]

				N. Zhang, W. Wei, I. Mody, and C. R. Houser Altered Localization of GABAA Receptor Subunits on Dentate Granule Cell Dendrites Influences Tonic and Phasic Inhibition in a Mouse Model of Epilepsy J. Neurosci., July 11, 2007; 27(28): 7520 - 7531. [Abstract] [Full Text] [PDF]

				B. Nahir, C. Bhatia, and C. J. Frazier Presynaptic Inhibition of Excitatory Afferents to Hilar Mossy Cells J Neurophysiol, June 1, 2007; 97(6): 4036 - 4047. [Abstract] [Full Text] [PDF]

				J. A. Gorter, E. A. van Vliet, E. Aronica, T. Breit, H. Rauwerda, F. H. Lopes da Silva, and W. J. Wadman Potential New Antiepileptogenic Targets Indicated by Microarray Analysis in a Rat Model for Temporal Lobe Epilepsy J. Neurosci., October 25, 2006; 26(43): 11083 - 11110. [Abstract] [Full Text] [PDF]

				B. K. Andrasfalvy and I. Mody Differences between the scaling of miniature IPSCs and EPSCs recorded in the dendrites of CA1 mouse pyramidal neurons J. Physiol., October 1, 2006; 576(1): 191 - 196. [Abstract] [Full Text] [PDF]