Phosphodiesterase 1B knock-out mice exhibit exaggerated locomotor hyperactivity and DARPP-32 phosphorylation in response to dopamine agonists and display impaired spatial learning.
Using homologous recombination, we generated mice lacking phosphodiesterase-mediated (PDE1B) cyclic nucleotide-hydrolyzing activity. PDE1B(-/-) mice showed exaggerated hyperactivity after acute D-methamphetamine administration. Striatal slices from PDE1B(-/-) mice exhibited increased levels of phospho-Thr34 DARPP-32 and phospho-Ser845 GluR1 after dopamine D1 receptor agonist or forskolin stimulation. PDE1B(-/-) and PDE1B(+/-) mice demonstrated Morris maze spatial-learning deficits. These results indicate that enhancement of cyclic nucleotide signaling by inactivation of PDE1B-mediated cyclic nucleotide hydrolysis plays a significant role in dopaminergic function through the DARPP-32 and related transduction pathways.
Reed
Tracy M
TM
Division of Developmental Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039, USA.
Repaske
David R
DR
Snyder
Gretchen L
GL
Greengard
Paul
P
Vorhees
Charles V
CV
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005260:Female; D018390:Gene Targeting; D007700:Kinetics; D008297:Male; D018782:Maze Learning; D008568:Memory; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000502:physiology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D017447:Receptors, Dopamine D1 / Q000819:agonists*
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017868:Cyclic AMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517267:Pde1b protein, mouse