Abstract

In mammals, identifying the contribution of specific neurons or networks to behavior is a key challenge. Here we describe an approach that facilitates this process by enabling the rapid modulation of synaptic inhibition in defined cell populations. Binding of zolpidem, a systemically active allosteric modulator that enhances the function of the GABA_A receptor, requires a phenylalanine residue (Phe77) in the 2 subunit. Mice in which this residue is changed to isoleucine are insensitive to zolpidem. By Cre recombinase–induced swapping of the 2 subunit (that is, exchanging Ile77 for Phe77), zolpidem sensitivity can be restored to GABA_A receptors in chosen cell types. We demonstrate the power of this method in the cerebellum, where zolpidem rapidly induces significant motor deficits when Purkinje cells are made uniquely sensitive to its action. This combined molecular and pharmacological technique has demonstrable advantages over targeted cell ablation and will be invaluable for investigating many neuronal circuits.

1. Department of Clinical Neurobiology, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
2. Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, POB 63 (Haartmaninkatu 8), University of Helsinki, FI-00014 Helsinki, Finland.
3. Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
4. MRC Anatomical Neuropharmacology Unit, Oxford University, Mansfield Road, Oxford OX1 3TH, UK.
5. Center for Brain Research, Section of Biochemistry and Molecular Biology of the Nervous System, Medical University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria.
6. Present address: Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
7. These authors contributed equally to this work.

Correspondence to: Peer Wulff^1,6,7 e-mail: p.wulff@abdn.ac.uk

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