Transgenic silencing of neurons in the mammalian brain by expression of the allatostatin receptor (AlstR)

M. Wehr, U. Hostick, M. Kyweriga, A. Tan, A. P. Weible, H. Wu, Wendy Wu, E. M. Callaway, C. Kentros

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The mammalian brain is an enormously complex set of circuits composed of interconnected neuronal cell types. The analysis of central neural circuits will be greatly served by the ability to turn off specific neuronal cell types while recording from others in intact brains. Because drug delivery cannot be restricted to specific cell types, this can only be achieved by putting "silencer" transgenes under the control of neuron-specific promoters. Towards this end we have created a line of transgenic mice putting the Drosophila allatostatin (AL) neuropeptide receptor (AlstR) under the control of the tetO element, thus enabling its inducible expression when crossed to tet-transactivator lines. Mammals have no endogenous AL or AlstR, but activation of exogenously expressed AlstR in mammalian neurons leads to membrane hyperpolarization via endogenous G-protein-coupled inward rectifier K + channels, making the neurons much less likely to fire action potentials. Here we show that this tetO/AlstR line is capable of broadly expressing AlstR mRNA in principal neurons throughout the forebrain when crossed to a commercially-available transactivator line. We electrophysiologically characterize this cross in hippocampal slices, demonstrating that bath application of AL leads to hyperpolarization of CA1 pyramidal neurons, making them refractory to the induction of action potentials by injected current. Finally, we demonstrate the ability of AL application to silence the sound-evoked spiking responses of auditory cortical neurons in intact brains of AlstR/tetO transgenic mice. When crossed to other transactivator lines expressing in defined neuronal cell types, this AlstR/tetO line should prove a very useful tool for the analysis of intact central neural circuits.

Original languageEnglish (US)
Pages (from-to)2554-2562
Number of pages9
JournalJournal of Neurophysiology
Volume102
Issue number4
DOIs
StatePublished - Oct 2009

Fingerprint

Neurons
Brain
Trans-Activators
Transgenic Mice
Action Potentials
allatostatin
Neuropeptide Receptors
Inwardly Rectifying Potassium Channel
Auditory Evoked Potentials
Pyramidal Cells
Prosencephalon
Transgenes
Baths
GTP-Binding Proteins
Mammals
Messenger RNA
Membranes
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Physiology
  • Neuroscience(all)

Cite this

Wehr, M., Hostick, U., Kyweriga, M., Tan, A., Weible, A. P., Wu, H., ... Kentros, C. (2009). Transgenic silencing of neurons in the mammalian brain by expression of the allatostatin receptor (AlstR). Journal of Neurophysiology, 102(4), 2554-2562. https://doi.org/10.1152/jn.00480.2009

Transgenic silencing of neurons in the mammalian brain by expression of the allatostatin receptor (AlstR). / Wehr, M.; Hostick, U.; Kyweriga, M.; Tan, A.; Weible, A. P.; Wu, H.; Wu, Wendy; Callaway, E. M.; Kentros, C.

In: Journal of Neurophysiology, Vol. 102, No. 4, 10.2009, p. 2554-2562.

Research output: Contribution to journalArticle

Wehr, M, Hostick, U, Kyweriga, M, Tan, A, Weible, AP, Wu, H, Wu, W, Callaway, EM & Kentros, C 2009, 'Transgenic silencing of neurons in the mammalian brain by expression of the allatostatin receptor (AlstR)', Journal of Neurophysiology, vol. 102, no. 4, pp. 2554-2562. https://doi.org/10.1152/jn.00480.2009
Wehr, M. ; Hostick, U. ; Kyweriga, M. ; Tan, A. ; Weible, A. P. ; Wu, H. ; Wu, Wendy ; Callaway, E. M. ; Kentros, C. / Transgenic silencing of neurons in the mammalian brain by expression of the allatostatin receptor (AlstR). In: Journal of Neurophysiology. 2009 ; Vol. 102, No. 4. pp. 2554-2562.
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