A Gαs DREADD mouse for selective modulation of cAMP production in striatopallidal neurons.
Journal Article (Journal Article)
Here, we describe a newly generated transgenic mouse in which the Gs DREADD (rM3Ds), an engineered G protein-coupled receptor, is selectively expressed in striatopallidal medium spiny neurons (MSNs). We first show that in vitro, rM3Ds can couple to Gαolf and induce cAMP accumulation in cultured neurons and HEK-T cells. The rM3Ds was then selectively and stably expressed in striatopallidal neurons by creating a transgenic mouse in which an adenosine2A (adora2a) receptor-containing bacterial artificial chromosome was employed to drive rM3Ds expression. In the adora2A-rM3Ds mouse, activation of rM3Ds by clozapine-N-oxide (CNO) induces DARPP-32 phosphorylation, consistent with the known consequence of activation of endogenous striatal Gαs-coupled GPCRs. We then tested whether CNO administration would produce behavioral responses associated with striatopallidal Gs signaling and in this regard CNO dose-dependently decreases spontaneous locomotor activity and inhibits novelty induced locomotor activity. Last, we show that CNO prevented behavioral sensitization to amphetamine and increased AMPAR/NMDAR ratios in transgene-expressing neurons of the nucleus accumbens shell. These studies demonstrate the utility of adora2a-rM3Ds transgenic mice for the selective and noninvasive modulation of Gαs signaling in specific neuronal populations in vivo.This unique tool provides a new resource for elucidating the roles of striatopallidal MSN Gαs signaling in other neurobehavioral contexts.
Full Text
Duke Authors
Cited Authors
- Farrell, MS; Pei, Y; Wan, Y; Yadav, PN; Daigle, TL; Urban, DJ; Lee, H-M; Sciaky, N; Simmons, A; Nonneman, RJ; Huang, X-P; Hufeisen, SJ; Guettier, J-M; Moy, SS; Wess, J; Caron, MG; Calakos, N; Roth, BL
Published Date
- April 2013
Published In
Volume / Issue
- 38 / 5
Start / End Page
- 854 - 862
PubMed ID
- 23303063
Pubmed Central ID
- PMC3671990
Electronic International Standard Serial Number (EISSN)
- 1740-634X
Digital Object Identifier (DOI)
- 10.1038/npp.2012.251
Language
- eng
Conference Location
- England