Extrasynaptic GABAA 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 GABAA receptors (GABAARs). Importantly, TC neurons also express extrasynaptic α4β2γ GABARs, although how they cooperate with synaptic GABAARs to influence relay cell inhibition, particularly during physiologically relevant nRT output, is unknown. To address this question, we performed paired wholecell recordings from synaptically couplednRTandTCneurons of the ventrobasal (VB) complex in brain slices derived from wild-type and extrasynaptic GABAAR-lacking, α40/0 "knock-out" (α40/0) mice. We demonstrate that the duration of VB phasic inhibition generated in response to nRT burst firing is greatly reduced in α40/0 pairs, suggesting that action potential-dependent phasic inhibition is prolonged by recruitment of extrasynapticGABAARs. Furthermore, the influence of nRT tonic firing frequency onVBholding current is also greatly reduced in α40/0 pairs, implying that the 4-GABAAR-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 GABAARs 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. © 2013 the authors.