Regulation of tyrosine phosphatase STEP61 by protein kinase A during motor skill learning in mice.
Recently, striatal-enriched protein tyrosine phosphatase (STEP) and its upstream regulator protein kinase A (PKA) have been suspected to play a role in the intracellular mechanisms of fear conditioning and spatial memory. However, whether they contribute to the learning and memory of motor skills is totally unknown. In this study, we have investigated the role of STEP and PKA activities during motor skill learning associated with the accelerating rotarod task. We observed that learning the rotarod task differentially modulated the levels of phosphorylated STEP61 at serine 221, a site directly regulated by PKA, in the hippocampus, motor cortex and striatum. In a second set of experiments, we have pharmacologically inhibited PKA by the injection of Rp-cAMPS directly into the dorsal striatum of mice before rotarod trainings. PKA phosphorylation of STEP prevents the dephosphorylation of STEP substrates, whereas inhibition of PKA promotes STEP activity. Striatal PKA inhibitions dose-dependently impaired mice performances on the accelerating rotarod task. General motor abilities testing revealed an intact motor control in mice treated with 5 and 20 µg of Rp-cAMPS, but not at the highest dose of 40 µg. This suggested that motor learning was selectively affected by PKA inhibition at lower doses. Most notably, striatal inhibition of PKA reduced the levels of phosphorylated STEP61 at serine 221. Our data support that inactivation of STEP61 by the PKA activity is part of the molecular process associated with motor skill learning.
Groupe de recherche en Neurosciences, Département de biologie médicale, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, Canada.
Laure
L
Chagniel
Groupe de recherche en Neurosciences, Département de biologie médicale, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, Canada.
Yan
Y
Bergeron
Groupe de recherche en Neurosciences, Département de biologie médicale, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, Canada.
Geneviève
G
Bureau
Groupe de recherche en Neurosciences, Département de biologie médicale, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, Canada.
Guy
G
Massicotte
Groupe de recherche en Neurosciences, Département de biologie médicale, Université du Québec à Trois-Rivières, Trois-Rivières, Québec, Canada.
Michel
M
Cyr
D000818:Animals; D015153:Blotting, Western; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009044:Motor Cortex / Q000187:drug effects / Q000378:metabolism*; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D013873:Thionucleotides / Q000494:pharmacology
D047428:Protein Kinase Inhibitors; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D017027:Protein Tyrosine Phosphatases; C000591055:striatal-enriched tyrosine phosphatase 61, mouse