Abstract
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.
Highlights
Motor skill learning refers to the process by which a complex movement sequence is encoded in the brain
The present study investigates the involvement of striatal-enriched protein tyrosine phosphatase (STEP) and its relationship with protein kinase A (PKA) in motor skill learning processes associated with the accelerating rotarod task in mice
We investigated whether motor skill learning influenced STEP phosphorylation at serine residue 221 (Ser221) for Striatal-enriched protein tyrosine phosphatase of 61 kDa (STEP61)
Summary
Motor skill learning refers to the process by which a complex movement sequence is encoded in the brain. The learning process associated with the acquisition of motor skills involves two stages (fast and slow learning stages) and brain areas including striatum, cerebellum, hippocampus and motor cortices regions [1,2]. Motor learning processes are mediated by specific brain molecular changes. It has been demonstrated that motor skill learning induces novel expressions of important genes and proteins in the striatum and motor cortex [3,4,5,6,7]. Only few studies have investigated motor learning at the level of proteins activity [6,8,9,10,11]. Additional investigations are definitely required to understand the molecular determinant of this type of learning
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