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NEUROSCIENCE |
1 Neurosciences Institute, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
2 Merck Research Laboratories, Merck & Co, 126 E. Lincoln Ave, Rahway, NJ 07065, USA
3 Department of Anaesthesiology and Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261, USA
The subunit composition of GABAA receptors influences their biophysical and pharmacological properties, dictates neuronal location and the interaction with associated proteins, and markedly influences the impact of intracellular biochemistry. The focus has been on 
and 
subunits, with little attention given to β subunits. Dentate gyrus granule cells (DGGCs) express all three β subunit isoforms and exhibit both synaptic and extrasynaptic receptors that mediate ‘phasic’ and ‘tonic’ transmission, respectively. To investigate the subcellular distribution of the β subunits we have utilized the patch-clamp technique to compare the properties of ‘tonic’ and miniature inhibitory postsynaptic currents (mIPSCs) recorded from DGGCs of hippocampal slices of P20–26 wild-type (WT), β2–/–, β2N265S (etomidate-insensitive), 1–/– and 
–/– mice. Deletion of either the β2 or the subunit produced a significant reduction of the tonic current and attenuated the increase of this current induced by the subunit-preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). By contrast, mIPSCs were not influenced by deletion of these genes. Enhancement of the tonic current by the β2/3 subunit-selective agent etomidate was significantly reduced for DGGCs derived from β2N265S mice, whereas this manipulation had no effect on the prolongation of mIPSCs produced by this anaesthetic. Collectively, these observations, together with previous studies on 4–/– mice, identify a population of extrasynaptic 4β2 receptors, whereas synaptic GABAA receptors appear to primarily incorporate the β3 subunit. A component of the tonic current is diazepam sensitive and is mediated by extrasynaptic receptors incorporating 5 and 2 subunits. Deletion of the β2 subunit had no effect on the diazepam-induced current and therefore these extrasynaptic receptors do not contain this subunit. The unambiguous identification of these distinct pools of synaptic and extrasynaptic GABAA receptors should aid our understanding of how they act in harmony, to regulate hippocampal signalling in health and disease.
(Received 16 October 2007;
accepted after revision 10 December 2007;
first published online 13 December 2007)
Corresponding author D. Belelli: Neurosciences Institute, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. Email: d.belelli{at}dundee.ac.uk
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