Defective motor behavior and neural gene expression in RIIbeta-protein kinase A mutant mice.
Motor behavior is modulated by dopamine-responsive neurons in the striatum, where dopaminergic signaling uses G-protein-coupled pathways, including those that result in the activation of cAMP-dependent protein kinase (PKA). The RIIbeta isoform of PKA is highly enriched in the striatum, and targeted disruption of the RIIbeta gene in mice leads to a dramatic reduction in total PKA activity in this region. Although the mutant mice show typical locomotor responses after acute administration of dopaminergic drugs, they display abnormalities in two experience-dependent locomotor behaviors: training on the rotarod task and locomotor sensitization to amphetamine. In addition, amphetamine induction of fos is absent, and the basal expression of dynorphin mRNA is reduced in the striatum. These results demonstrate that motor learning and the regulation of neuronal gene expression require RIIbeta PKA, whereas the acute locomotor effects of dopaminergic drugs are relatively unaffected by this PKA deficiency.
Brandon
E P
EP
Department of Pharmacology, School of Medicine, University of Washington, Seattle, Washington 98195, USA.
Logue
S F
SF
Adams
M R
MR
Qi
M
M
Sullivan
S P
SP
Matsumoto
A M
AM
Dorsa
D M
DM
Wehner
J M
JM
McKnight
G S
GS
Idzerda
R L
RL
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000235:genetics; D005298:Fertility / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008136:Longevity / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000201:enzymology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism
D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D015259:Dopamine Agents; D007527:Isoenzymes; C517838:Prkar2b protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D004399:Dynorphins; D000661:Amphetamine; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine