title: A Gαs DREADD mouse for selective modulation of cAMP production in striatopallidal neurons.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Martilias S
authors.initials: MS
authors.lastname: Farrell
authors.forename: Ying
authors.initials: Y
authors.lastname: Pei
authors.forename: Yehong
authors.initials: Y
authors.lastname: Wan
authors.forename: Prem N
authors.initials: PN
authors.lastname: Yadav
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Daigle
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Urban
authors.forename: Hyeong-Min
authors.initials: HM
authors.lastname: Lee
authors.forename: Noah
authors.initials: N
authors.lastname: Sciaky
authors.forename: Arkeen
authors.initials: A
authors.lastname: Simmons
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Nonneman
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: Sandy J
authors.initials: SJ
authors.lastname: Hufeisen
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Guettier
authors.forename: Sheryl S
authors.initials: SS
authors.lastname: Moy
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.forename: Nicole
authors.initials: N
authors.lastname: Calakos
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology*; D000242:Cyclic AMP / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D043705:Receptor, Adenosine A2A / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D011976:Receptors, Muscarinic / Q000235:genetics*; D000097573:Red Fluorescent Protein
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000661:Amphetamine; D003024:Clozapine; D003042:Cocaine; D000242:Cyclic AMP; D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D019205:GTP-Binding Protein alpha Subunits, Gs; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D011976:Receptors, Muscarinic; D000097573:Red Fluorescent Protein; C079149:clozapine N-oxide