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Technical Report

Nature Neuroscience 10, 923–929 (1 July 2007) | doi:10.1038/nn1927

From synapse to behavior: rapid modulation of defined neuronal types with engineered GABAA receptors

Peer Wulff , Thomas Goetz , Elli Lepp|[auml]| , Anni-Maija Linden , Massimiliano Renzi , Jerome D Swinny , Olga Y Vekovischeva , Werner Sieghart , Peter Somogyi , Esa R Korpi , Mark Farrant & William Wisden

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 GABAA receptor, requires a phenylalanine residue (Phe77) in the γ2 subunit. Mice in which this residue is changed to isoleucine are insensitive to zolpidem. By Cre recombinase–induced swapping of the γ2 subunit (that is, exchanging Ile77 for Phe77), zolpidem sensitivity can be restored to GABAA 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.