In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 34, No. 49 ( 2014-12-03), p. 16256-16272
Abstract:
In the present study, the orthosteric GABA A receptor (GABA A R) ligand 4,5,6,7-tetrahydroisothiazolo[5,4- c ]pyridin-3-ol (Thio-THIP) was found to possess a highly interesting functional profile at recombinant human GABA A Rs and native rat GABA A Rs. Whereas Thio-THIP displayed weak antagonist activity at α 1,2,5 β 2,3 γ 2S and ρ 1 GABA A Rs and partial agonism at α 6 β 2,3 δ GABA A Rs expressed in Xenopus oocytes, the pronounced agonism exhibited by the compound at α 4 β 1 δ and α 4 β 3 δ GABA A Rs was contrasted by its negligible activity at the α 4 β 2 δ subtype. To elucidate to which extent this in vitro profile translated into functionality at native GABA A Rs, we assessed the effects of 100 μ m Thio-THIP at synaptic and extrasynaptic receptors in principal cells of four different brain regions by slice electrophysiology. In concordance with its α 6 β 2,3 δ agonism, Thio-THIP evoked robust currents through extrasynaptic GABA A Rs in cerebellar granule cells. In contrast, the compound did not elicit significant currents in dentate gyrus granule cells or in striatal medium spiny neurons (MSNs), indicating predominant expression of extrasynaptic α 4 β 2 δ receptors in these cells. Interestingly, Thio-THIP evoked differential degrees of currents in ventrobasal thalamus neurons, a diversity that could arise from differential expression of extrasynaptic α 4 βδ subtypes in the cells. Finally, whereas 100 μ m Thio-THIP did not affect the synaptic currents in ventrobasal thalamus neurons or striatal MSNs, it reduced the current amplitudes recorded from dentate gyrus granule cells, most likely by targeting perisynaptic α 4 βδ receptors expressed at distal dendrites of these cells. Being the first published ligand capable of discriminating between β 2 - and β 3 -containing receptor subtypes, Thio-THIP could be a valuable tool in explorations of native α 4 βδ GABA A Rs.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.1495-14.2014
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2014
detail.hit.zdb_id:
1475274-8
SSG:
12
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