Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c] pyridine-3-ol: A selective role for δ-GABA_A receptors

The sedative and hypnotic agent 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine- 3-ol (THIP) is a GABA_A receptor (GABA_AR) agonist that preferentially activates δ-subunit-containing GABA_ARs (δ-GABA_ARs). To clarify the role of δ-GABA_ARs in mediating the sedative actions of THIP, we utilized mice lacking the α₁- or δ-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 GABA _AR-mediated tonic current of 92 ± 19 pA, which was greatly reduced (13 ± 5 pA) for VB neurones of δ^0/0 mice. Deletion of the δ- but not the α₁-subunit dramatically reduced the THIP (1 μm)-induced inward current in these neurones (WT, -309 ± 23 pA; δ^0/0, -18 ± 3 pA; α ₁^0/0, -377 ± 45 pA). Furthermore, THIP selectively decreased the excitability of WT and α₁^0/0 but not δ^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 δ^0/0 but not α₁^0/0 mice. We previously reported that deletion of the α₁-subunit abolished synaptic GABA_A responses of VB neurones. Therefore, collectively, these findings suggest that extrasynaptic δ-GABA _ARs vs. synaptic α₁-subunit-containing GABA _ARs of thalamocortical neurones represent an important molecular target underpinning the sedative actions of THIP.