Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for delta-GABA(A) receptors.

The sedative and hypnotic agent 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP) is a GABAA receptor (GABAAR) agonist that preferentially activates d-subunit-containing GABAARs (d-GABAARs). To clarify the role of d-GABAARs in mediating the sedative actions of THIP, we utilized mice lacking the a1 -o rd-subunit in a combined electrophysiological and behavioural analysis. Whole-cell patch-clamp recordings were obtained from ventrobasal thalamic nucleus (VB) neurones at a holding potential of )60 mV. Application of bicuculline to wild-type (WT) VB neurones revealed a GABAAR-mediated tonic current of 92 ± 19 pA, which was greatly reduced (13 ± 5 pA) for VB neurones of d 0 ⁄ 0 mice. Deletion of the d- but not the a1-subunit dramatically reduced the THIP (1 lm)-induced inward current in these neurones (WT, )309 ± 23 pA; d 0 ⁄ 0 , )18 ± 3 pA; a1 0 ⁄ 0 , )377 ± 45 pA). Furthermore, THIP selectively decreased the excitability of WT and a1 0 ⁄ 0 but not d 0 ⁄ 0 VB neurones. THIP did not affect the properties of miniature inhibitory post-synaptic currents in any of the genotypes. No differences in rotarod performance and locomotor activity were observed across the three genotypes. In WT mice, performance of these behaviours was impaired by THIP in a dose-dependent manner. The effect of THIP on rotarod performance was blunted for d 0 ⁄ 0 but not a1 0 ⁄ 0 mice. We previously reported that deletion of the a1-subunit abolished synaptic GABAA responses of VB neurones. Therefore, collectively, these findings suggest that extrasynaptic d-GABAARs vs. synaptic a1-subunit-containing GABAARs of thalamocortical neurones represent an important molecular target underpinning the sedative actions of THIP.