A Gαs DREADD Mouse for Selective Modulation of cAMP Production in Striatopallidal Neurons

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 neur...

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Published in:Neuropsychopharmacology (New York, N.Y.) N.Y.), 2013-04, Vol.38 (5), p.854-862
Main Authors: FARRELL, Martilias S, YING PEI, HUANG, Xi-Ping, HUFEISEN, Sandy J, GUETTIER, Jean-Marc, MOY, Sheryl S, WESS, Jürgen, CARON, Marc G, CALAKOS, Nicole, ROTH, Bryan L, YEHONG WAN, YADAV, Prem N, DAIGLE, Tanya L, URBAN, Daniel J, LEE, Hyeong-Min, SCIAKY, Noah, SIMMONS, Arkeen, NONNEMAN, Randal J
Format: Article
Language:English
Subjects:
Adrenergic Uptake Inhibitors - pharmacology
Amphetamine - pharmacology
Animals
Animals, Newborn
Biological and medical sciences
Clozapine - analogs & derivatives
Clozapine - pharmacology
Cocaine - pharmacology
Corpus Striatum - cytology
Cyclic AMP - metabolism
Dopamine and cAMP-Regulated Phosphoprotein 32 - metabolism
Dopamine Uptake Inhibitors - pharmacology
Green Fluorescent Proteins - genetics
GTP-Binding Protein alpha Subunits, Gs - genetics
Locomotion - drug effects
Locomotion - genetics
Luminescent Proteins - genetics
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurons - metabolism
Neuropharmacology
Original
Pharmacology. Drug treatments
Phosphorylation - drug effects
Phosphorylation - genetics
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Receptor, Adenosine A2A - genetics
Receptors, Dopamine D1 - genetics
Receptors, Dopamine D2 - genetics
Receptors, G-Protein-Coupled - genetics
Receptors, Muscarinic - genetics
Red Fluorescent Protein
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Summary: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.
ISSN:0893-133X
1740-634X
DOI:10.1038/npp.2012.251