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Dynamic mobility of functional GABAA receptors at inhibitory synapses

Nature Neuroscience volume 8, pages 889–897 (2005)Cite this article

Abstract

Importing functional GABAA receptors into synapses is fundamental for establishing and maintaining inhibitory transmission and for controlling neuronal excitability. By introducing a binding site for an irreversible inhibitor into the GABAA receptor α1 subunit channel lining region that can be accessed only when the receptor is activated, we have determined the dynamics of receptor mobility between synaptic and extrasynaptic locations in hippocampal pyramidal neurons. We demonstrate that the cell surface GABAA receptor population shows no fast recovery after irreversible inhibition. In contrast, after selective inhibition, the synaptic receptor population rapidly recovers by the import of new functional entities within minutes. The trafficking pathways that promote rapid importation of synaptic receptors do not involve insertion from intracellular pools, but reflect receptor diffusion within the plane of the membrane. This process offers the synapse a rapid mechanism to replenish functional GABAA receptors at inhibitory synapses and a means to control synaptic efficacy.

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Figure 1: MTSES block of recombinant α1V257Cβ2γ2 GABAA receptors in HEK293 cells.
Figure 2: MTSES sensitivity of open and closed recombinant GABAA receptors in HEK293 cells.
Figure 3: Expressing functional mutant α1V257C-containing receptors in hippocampal neurons.
Figure 4: Synaptic GABAA receptor currents incorporating the α1V257C subunit in hippocampal neurons.
Figure 5: Evoked IPSCs in hippocampal neurons expressing α1V257C.
Figure 6: Non-stationary noise and kinetic analyses of synaptic GABAA receptors in α1V257C subunit–expressing hippocampal neurons.
Figure 7: Synaptic receptor mobility does not involve insertion from intracellular pools.

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Acknowledgements

We thank S. Wallace (UK Medical Research Council Ph.D. student) for assistance and I. Duguid and A. Gibb for helpful comments and discussions. This work was supported by the UK Medical Research Council and the Wellcome Trust.

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Authors and Affiliations

  1. Department of Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK

    Philip Thomas, Martin Mortensen, Alastair M Hosie & Trevor G Smart

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Correspondence to Trevor G Smart.

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Supplementary information

Supplementary Fig. 1

Tracking the mobility of synaptic GABAA receptors in neurons. (GIF 33 kb)

Supplementary Fig. 2

Single cell time-course changes in mIPSC amplitudes for two representative hippocampal cells transfected with α1V257C. (GIF 18 kb)

Supplementary Fig. 3

Mobility of GABAA receptors in neurons. (GIF 26 kb)

Supplementary Methods (PDF 85 kb)

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Thomas, P., Mortensen, M., Hosie, A. et al. Dynamic mobility of functional GABAA receptors at inhibitory synapses. Nat Neurosci 8, 889–897 (2005). https://doi.org/10.1038/nn1483

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