Enzyme Deficient Mice Display Hyperactivity and Impaired Learning Ability

Tracy M. Reed and Charles V. Vorhees
Children's Hospital Medical Center, Cincinnati, Ohio
T32ES07051

Background: The family of calcium/calmodulin dependent phosphodiesterases (CaM-PDE) act as a potential point of interaction between the Ca2+ and cyclic nucleotide signaling pathways. The three known CaM-PDE genes PDE1A-C, are expressed in the central nervous system. PDE1A is expressed throughout the brain with high levels in the cerebellum and lower levels in the striatum. PDE1B is expressed predominantly in regions of the brain with high dopaminergic innervation such as the striatum and cerebellum. PDE1C is also expressed predominantly in the striatum. The expression of these genes in the striatum and other evidence that cyclic nucleotides and calcium are principal second messengers of the signal transduction pathways in the striatum suggest that CaM-PDEs may play a role in motor control. To investigate this hypothesis, these investigators generated knock-out mice lacking the PDE1B gene.

Advance: These mice showed increased hyperactivity, as compared to normal mice, after acute exposure to D-methamphetamine. Since the mice lacked the enzyme, hydrolysis of the cyclic nucleotides could not occur and was confirmed with analysis of tissue slices. The knock out mice and mice with one copy of the functioning gene demonstrated spatial-learning deficits in experiments employing a Morris maze.

Implication: These results indicate that enhancement of cyclic nucleotide signaling by inactivation of PDE1B-mediated cyclic nucleotide hydrolysis plays a major role in dopaminergic function. The results of these experiments support the conclusion that regulation of intracellular cyclic nucleotide concentration is important in the cellular processes that underlie learning and memory.

Citation: Reed TM, Repaske DR, Snyder GL, Greengard P, Vorhees, CV. Phosphodiesterase 1B knock-out mice exhibit exaggerated locomotor hyperactivity and DARPP-32 phosphorylation in response to dopamine agonists and displayed impaired spatial learning. Journal of Neuroscience, June 15, 2002; 22(12):5188-5197.