Abstract
We have made use of the δ subunit-selective allosteric modulator DS2 (4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridine-3-yl benzamide) to assay the contribution of δ-GABAARs to tonic and phasic conductance changes in the cerebellum, thalamus and neocortex. In cerebellar granule cells, an enhancement of the tonic conductance was observed for DS2 and the orthosteric agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol). As expected, DS2 did not alter the properties of GABAA receptor-mediated inhibitory postsynaptic synaptic conductances (IPSCs) supporting a purely extrasynaptic role for δ-GABAARs in cerebellar granule cells. DS2 also enhanced the tonic conductance recorded from thalamic relay neurons of the visual thalamus with no alteration in IPSC properties. However, in addition to enhancing the tonic conductance DS2 also slowed the decay of IPSCs recorded from layer II/III neocortical neurons. A slowing of the IPSC decay also occurred in the presence of the voltage-gated sodium channel blocker TTX. Moreover, under conditions of reduced GABA release the ability of DS2 to enhance the tonic conductance was attenuated. These results indicate that δ-GABAARs can be activated following vesicular GABA release onto neocortical neurons and that the actions of DS2 on the tonic conductance may be influenced by the ambient GABA levels present in particular brain regions.
Highlights
GABAA receptor heterogeneity influences the excitability of specific neuronal populations and is a major determinant of the drug sensitivity of different brain regions
DS2 is expected to enhance the tonic conductance generated by the persistent activation of high-affinity δ-GABAARs with little action on inhibitory postsynaptic synaptic conductances (IPSCs) mediated by conventional synaptic γGABAARs
We initially compared the actions of DS2 with the more commonly used δ-GABAAR selective orthosteric agonist, THIP
Summary
GABAA receptor heterogeneity influences the excitability of specific neuronal populations and is a major determinant of the drug sensitivity of different brain regions. The discovery of the δ-GABAAR (Shivers et al, 1989; Wisden et al, 1992) led to the view that low ambient GABA levels in the extracellular space (Kekesi et al, 1997; Wu et al, 2007) was capable of generating a novel form of tonic inhibition in brain regions that expressed δ-GABAARs (Kaneda et al, 1995; Salin and Prince, 1996; Brickley et al, 2001; Stell et al, 2003; Drasbek and Jensen, 2006; Bright et al, 2007; Ade et al, 2008; Kirmse et al, 2008; Santhakumar et al, 2010) This particular member of the GABAA receptor family has attracted clinical interest because the δ-GABAAR orthosteric agonist THIP has been shown to promote the slow thalamocortical oscillations associated with sleep (Faulhaber et al, 1997; Cope et al, 2005; Winsky-Sommerer et al, 2007). This drug has the potential to assay the involvement of functionally relevant δ-GABAARs in the generation of tonic and phasic conductance changes
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