Inhibition of thalamic excitability by 4,5,6,7‐tetrahydroisoxazolo[4,5‐c]pyridine‐3‐ol: a selective role for δ‐GABAAreceptors

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Abstract
The sedative and hypnotic agent 4,5,6,7‐tetrahydroisoxazolo[4,5‐c]pyridine‐3‐ol (THIP) is a GABAAreceptor (GABAAR) agonist that preferentially activates δ‐subunit‐containing GABAARs (δ‐GABAARs). To clarify the role of δ‐GABAARs 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 GABAAR‐mediated tonic current of 92 ± 19 pA, which was greatly reduced (13 ± 5 pA) for VB neurones of δ0/0mice. 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; δ0/0, −18 ± 3 pA; α10/0, −377 ± 45 pA). Furthermore, THIP selectively decreased the excitability of WT and α10/0but not δ0/0VB 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 δ0/0but not α10/0mice. We previously reported that deletion of the α1‐subunit abolished synaptic GABAAresponses of VB neurones. Therefore, collectively, these findings suggest that extrasynaptic δ‐GABAARs vs. synaptic α1‐subunit‐containing GABAARs of thalamocortical neurones represent an important molecular target underpinning the sedative actions of THIP.

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