Extrasynaptic GABA(A) receptors couple presynaptic activity to postsynaptic inhibition in the somatosensory thalamus

Murray Herd, Adam R. Brown, Jeremy Lambert, Delia Belelli

    Research output: Contribution to journalArticlepeer-review

    53 Citations (Scopus)

    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 a1ß2?2 GABAA receptors (GABAARs). Importantly, TC neurons also express extrasynaptic a4ß2d GABAARs, 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 whole-cell recordings from synaptically coupled nRT and TC neurons of the ventrobasal (VB) complex in brain slices derived from wild-type and extrasynaptic GABAAR-lacking, a4 “knock-out” (a40/0) mice. We demonstrate that the duration of VB phasic inhibition generated in response to nRT burst firing is greatly reduced in a40/0 pairs, suggesting that action potential-dependent phasic inhibition is prolonged by recruitment of extrasynaptic GABAARs. Furthermore, the influence of nRT tonic firing frequency on VB holding current is also greatly reduced in a40/0 pairs, implying that the a4-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 d-selective allosteric modulator, DS2 and manipulation of GABA transport systems, revealing novel opportunities for therapeutic intervention in thalamocortical network disorders.
    Original languageEnglish
    Pages (from-to)14850-14868
    JournalJournal of Neuroscience
    Volume33
    Issue number37
    DOIs
    Publication statusPublished - 11 Sep 2013

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