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The Journal of Neuroscience, May 15, 1998, 18(10):3639-3649

Defective Motor Behavior and Neural Gene Expression in RII-Protein Kinase A Mutant Mice

Eugene P. Brandon¹, Sheree F. Logue⁴, Monique R. Adams¹, Ming Qi¹, Sean P. Sullivan¹, Alvin M. Matsumoto², Daniel M. Dorsa^{1, 3}, Jeanne M. Wehner⁴, G. Stanley McKnight¹, and Rejean L. Idzerda¹

Departments of ¹ Pharmacology, ² Medicine and the Geriatric Research Education and Clinical Center of the Veterans Affairs Puget Sound Health Care System, and ³ Psychiatry and Behavioral Science, School of Medicine, University of Washington, Seattle, Washington 98195, and ⁴ Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado 80309

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 RII isoform of PKA is highly enriched in the striatum, and targeted disruption of the RII 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 RII PKA, whereas the acute locomotor effects of dopaminergic drugs are relatively unaffected by this PKA deficiency.

Key words: cAMP-dependent protein kinase; PKA; knock-out; mouse; striatum; dopamine; amphetamine; locomotion; rotarod; sensitization; fos; dynorphin

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18103639-11$05.00/0

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