Phosphodiesterase 1B Knock-Out Mice Exhibit Exaggerated Locomotor Hyperactivity and DARPP-32 Phosphorylation in Response to Dopamine Agonists and Display Impaired Spatial Learning

摘要

Using homologous recombination, we generated mice lacking phosphodiesterase-mediated (PDE1B) cyclic nucleotide-hydrolyzing activity. PDE1B^−/− mice showed exaggerated hyperactivity after acuted-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.