title: Extrasynaptic GABA(A) receptors couple presynaptic activity to postsynaptic inhibition in the somatosensory thalamus.
abstract: Thalamocortical circuits govern cognitive, sensorimotor, and sleep-related network processes, and generate pathological activities during absence epilepsy. Inhibitory control of thalamocortical (TC) relay neurons is partially mediated by GABA released from neurons of the thalamic reticular nucleus (nRT), acting predominantly via synaptic α1β2γ2 GABA(A) receptors (GABA(A)Rs). Importantly, TC neurons also express extrasynaptic α4β2δ GABA(A)Rs, although how they cooperate with synaptic GABA(A)Rs to influence relay cell inhibition, particularly during physiologically relevant nRT output, is unknown. To address this question, we performed paired whole-cell recordings from synaptically coupled nRT and TC neurons of the ventrobasal (VB) complex in brain slices derived from wild-type and extrasynaptic GABA(A)R-lacking, α4 "knock-out" (α4(0/0)) mice. We demonstrate that the duration of VB phasic inhibition generated in response to nRT burst firing is greatly reduced in α4(0/0) pairs, suggesting that action potential-dependent phasic inhibition is prolonged by recruitment of extrasynaptic GABA(A)Rs. Furthermore, the influence of nRT tonic firing frequency on VB holding current is also greatly reduced in α4(0/0) pairs, implying that the α4-GABA(A)R-mediated tonic conductance of relay neurons is dynamically influenced, in an activity-dependent manner, by nRT tonic firing intensity. Collectively, our data reveal that extrasynaptic GABA(A)Rs of the somatosensory thalamus do not merely provide static tonic inhibition but can also be dynamically engaged to couple presynaptic activity to postsynaptic excitability. Moreover, these processes are highly sensitive to the δ-selective allosteric modulator, DS2 and manipulation of GABA transport systems, revealing novel opportunities for therapeutic intervention in thalamocortical network disorders.
authors.affiliation: Division of Neuroscience, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom.
authors.forename: Murray B
authors.initials: MB
authors.lastname: Herd
authors.forename: Adam R
authors.initials: AR
authors.lastname: Brown
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Lambert
authors.forename: Delia
authors.initials: D
authors.lastname: Belelli
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D003198:Computer Simulation; D004558:Electric Stimulation; D018682:GABA Agents / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008959:Models, Neurological; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009557:Nipecotic Acids / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013788:Thalamus / Q000166:cytology*; D015645:Tylosin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C114856:4-'demycarosyl-20-deoxo-20-(di-N-benzylamino)-8a-aza-8a-homotylosin; D018682:GABA Agents; D050485:GABA Plasma Membrane Transport Proteins; D009557:Nipecotic Acids; D011963:Receptors, GABA-A; C030278:nipecotic acid; D015645:Tylosin
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