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

Wulff, P; Goetz, T; Leppa, E; Linden, AM; Renzi, M; Swinny, JD; Vekovischeva, OY; ... Wisden, W; + view all (2007) From synapse to behavior: rapid modulation of defined neuronal types with engineered GABAA receptors. NAT NEUROSCI , 10 (7) 923 - 929. 10.1038/nn1927.

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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 GABAA receptor, requires a phenylalanine residue (Phe77) in the gamma 2 subunit. Mice in which this residue is changed to isoleucine are insensitive to zolpidem. By Cre recombinase-induced swapping of the gamma 2 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.

Type: Article
Title: From synapse to behavior: rapid modulation of defined neuronal types with engineered GABAA receptors
DOI: 10.1038/nn1927
Keywords: CEREBELLAR PURKINJE-CELLS, AMINOBUTYRIC ACID(A) RECEPTOR, ZOLPIDEM BINDING-SITES, SUBUNIT MESSENGER-RNAS, POINT MUTATION, RAT-BRAIN, IN-VIVO, REVERSIBLE INACTIVATION, BENZODIAZEPINE SITE, NEURAL CIRCUITRY
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/120336
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