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First published online on December 6, 2007.
Copyright © 2007 by The Physiological Society
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jphysiol.2007.145375v1
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Received September 23, 2007
Revised October 18, 2007
Accepted after revision November 30, 2007

Developmental maturation of synaptic and extrasynaptic GABAA receptors in mouse thalamic ventrobasal neurones

Dianne R Peden1, Caroline M Petitjean2, Murray B Herd1, Murat Durakoglugil1, Thomas W Rosahl3, Keith Wafford3, Gregg E Homanics4, Delia Belelli1, Jean-Marc Fritschy5, and Jeremy J Lambert1*

1 University of Dundee, Neurosciences Institute
2 Univerisity of Zurich, Institute of Pharmacology and Toxicology
3 Merck & Co
4 University of Pittsburgh
5 Univeristy of Zurich, Institute of Pharmacology and Toxicology

* To whom correspondence should be addressed. E-mail: j.j.lambert{at}dundee.ac.uk.

Thalamic ventrobasal (VB) relay neurones express multiple GABAA receptor subtypes mediating phasic and tonic inhibition. During postnatal development, marked changes in subunit expression occur, presumably reflecting changes in functional properties of neuronal networks. The aims of this study were to characterize the properties of synaptic and extrasynaptic GABAA receptors of developing VB neurones and investigate the role of the {alpha}1 subunit during maturation of GABA-ergic transmission, using electrophysiology and immunohistochemistry in wild type (WT) and {alpha}10/0 mice and mice engineered to express diazepam-insensitive receptors ({alpha}1H101R,{alpha}2H101R). In immature brain, rapid (P8/9-P10/11) developmental change to mIPSC kinetics and increased expression of extrasynaptic receptors (P8-27) formed by the {alpha}4 and {delta} subunit occurred independently of the {alpha}1 subunit. Subsequently, (≥P15), synaptic {alpha}2 subunit/gephyrin clusters of WT VB neurones were replaced by those containing the {alpha}1 subunit. Surprisingly, in {alpha}10/0 VB neurones the frequency of mIPSCs decreased between P12-27 , because the {alpha}2 subunit also disappeared from these cells. The loss of synaptic GABAA receptors led to a delayed disruption of gephyrin clusters. Despite these alterations, GABA-ergic terminals were preserved, perhaps maintaining tonic inhibition. These results demonstrate that maturation of synaptic and extrasynaptic GABAA receptors in VB follows a developmental program independent of the {alpha}1 subunit. Changes to synaptic GABAA receptor function, coupled with the increased expression of extrasynaptic GABAA receptors, represent two distinct mechanisms for fine-tuning GABA-ergic control of thalamic relay neurone activity during development.


Key words: Thalamus • extrasynaptic GABAA receptors • synaptic GABAA receptors




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