From synapse to behaviour: Rapid modulation of defined neuronal types with engineered GABA-A receptors

Peer Wulff, Thomas Goetz, Elli Leppä, Anni-Maija Linden, Massimiliano Renzi, Jerome D. Swinny, Olga Y. Vekovischeva, Werner Sieghart, Peter Somogyi, Esa R. Korpi, Mark Farrant, William Wisden

Research output: Contribution to journalArticle

88 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)923-929
Number of pages7
JournalNature Neuroscience
Volume10
Issue number7
DOIs
Publication statusPublished - Jun 2007

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

Cite this

Wulff, P., Goetz, T., Leppä, E., Linden, A-M., Renzi, M., Swinny, J. D., Vekovischeva, O. Y., Sieghart, W., Somogyi, P., Korpi, E. R., Farrant, M., & Wisden, W. (2007). From synapse to behaviour: Rapid modulation of defined neuronal types with engineered GABA-A receptors. Nature Neuroscience, 10(7), 923-929. https://doi.org/10.1038/NN1927