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Dopamine Promotes Motor Cortex Plasticity and Motor Skill Learning via PLC Activation.

Rioult-Pedotti MS, Pekanovic A, Atiemo CO, Marshall J, Luft AR - PLoS ONE (2015)

Bottom Line: Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation.Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist.These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors.

View Article: PubMed Central - PubMed

Affiliation: Clinical Neurorehabilitation, Department of Neurology, University of Zurich, Zurich, Switzerland; Rehabilitation Initiative and Technology Center Zurich (RITZ), Zurich, Switzerland; Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, United States of America.

ABSTRACT
Dopaminergic neurons in the ventral tegmental area, the major midbrain nucleus projecting to the motor cortex, play a key role in motor skill learning and motor cortex synaptic plasticity. Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation. Traditionally, D1 and D2 receptor modulate adenylyl cyclase activity and cyclic adenosine monophosphate accumulation in opposite directions via different G-proteins and bidirectionally modulate protein kinase A (PKA), leading to distinct physiological and behavioral effects. Here we show that D1 and D2 receptor activity influences motor skill acquisition and long term synaptic potentiation via phospholipase C (PLC) activation in rat primary motor cortex. Learning a new forelimb reaching task is severely impaired in the presence of PLC, but not PKA-inhibitor. Similarly, long term potentiation in motor cortex, a mechanism involved in motor skill learning, is reduced when PLC is inhibited but remains unaffected by the PKA inhibitor. Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist. These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors. These findings reveal a novel and important action of dopamine in motor cortex that might be a future target for selective therapeutic interventions to support learning and recovery of movement resulting from injury and disease.

No MeSH data available.


Related in: MedlinePlus

Experimental design.(a) Timeline for experiments shown in Fig 2A using continuous drug release via minipump (red bar) during motor skill training. (b) Timeline for experiments shown in Fig 2B, Fig 3A and 3B using acute drug injections on day 2 and 3 of motor skill training (red arrows). (c) Timeline for experiments shown in Fig 2 using continuous drug release via minipump (red bar) after successful acquisition of the motor task.
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pone.0124986.g001: Experimental design.(a) Timeline for experiments shown in Fig 2A using continuous drug release via minipump (red bar) during motor skill training. (b) Timeline for experiments shown in Fig 2B, Fig 3A and 3B using acute drug injections on day 2 and 3 of motor skill training (red arrows). (c) Timeline for experiments shown in Fig 2 using continuous drug release via minipump (red bar) after successful acquisition of the motor task.

Mentions: To establish whether DA activates intracellular PKA and/or PLC signaling pathways in M1 specific inhibitors were continuously infused directly into the M1 forelimb area of adult rats via osmotic minipumps while the animals were learning a new motor skill (Fig 1A). Rats were trained to reach with a single forepaw through a small aperture to reach and grasp single food pellets for 8 successive days. Learning curves as illustrated in Fig 2 indicate a significant impairment of skill acquisition in animals that received intracortical infusion of the PLC inhibitor U73122 while infusion of PKA inhibitor H89 had no effect (N = 6 per inhibitor, N = 12 controls; interaction of group by time: F (16, 168) = 2.557, p = 0.0015, significant post-hoc Dunnetts‘s tests for comparison between PLC inhibitor and control for training session 5: mean difference -14.26 (CI -26.55 to -1.977); session 6: -19.30 (CI -31.59 to -7.016); session 7: -13.35 (CI -25.64 to -1.067); and session 9:, -13.43 (CI -25.71 to -1.141); Fig 2A left). Time intervals between reaching trials were used as a measure of motivation. They were significantly longer in all training sessions in PLC inhibitor-treated rats as compared with vehicle-treated controls but were unaffected in PKA inhibitor-treated rats (main effect of group: F (2, 20) = 7.398, p = 0.0039, significant post-hoc Dunnett‘s tests for comparison between PLC inhibitor and control: session 3: mean difference 7.910 (CI 2.891 to 12.93); session 4: 5.970 (CI 0.9507 to 10.99); and session 6: 6.978 (CI 1.959 to 12.00); Fig 2A right). Similar results were achieved when the drugs were applied via implanted cannulas during the steepest part of the learning curve, on day 2 and 3 of skill training (30 minutes prior to training; Fig 1B). Skill acquisition was impaired in the presence of PLC- but not PKA inhibitor compared to control rats (Fig 2B). This data set revealed a significant interaction of group and time (F (12, 150) = 1.980, p = 0.0297), but post hoc tests comparing the groups individually to control were not significant (p>0.8). There were no differences between groups with respect to the time intervals between reaching trials. The inset in Fig 2B emphasizes the lack of success improvement between days 2 and 3.


Dopamine Promotes Motor Cortex Plasticity and Motor Skill Learning via PLC Activation.

Rioult-Pedotti MS, Pekanovic A, Atiemo CO, Marshall J, Luft AR - PLoS ONE (2015)

Experimental design.(a) Timeline for experiments shown in Fig 2A using continuous drug release via minipump (red bar) during motor skill training. (b) Timeline for experiments shown in Fig 2B, Fig 3A and 3B using acute drug injections on day 2 and 3 of motor skill training (red arrows). (c) Timeline for experiments shown in Fig 2 using continuous drug release via minipump (red bar) after successful acquisition of the motor task.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4418826&req=5

pone.0124986.g001: Experimental design.(a) Timeline for experiments shown in Fig 2A using continuous drug release via minipump (red bar) during motor skill training. (b) Timeline for experiments shown in Fig 2B, Fig 3A and 3B using acute drug injections on day 2 and 3 of motor skill training (red arrows). (c) Timeline for experiments shown in Fig 2 using continuous drug release via minipump (red bar) after successful acquisition of the motor task.
Mentions: To establish whether DA activates intracellular PKA and/or PLC signaling pathways in M1 specific inhibitors were continuously infused directly into the M1 forelimb area of adult rats via osmotic minipumps while the animals were learning a new motor skill (Fig 1A). Rats were trained to reach with a single forepaw through a small aperture to reach and grasp single food pellets for 8 successive days. Learning curves as illustrated in Fig 2 indicate a significant impairment of skill acquisition in animals that received intracortical infusion of the PLC inhibitor U73122 while infusion of PKA inhibitor H89 had no effect (N = 6 per inhibitor, N = 12 controls; interaction of group by time: F (16, 168) = 2.557, p = 0.0015, significant post-hoc Dunnetts‘s tests for comparison between PLC inhibitor and control for training session 5: mean difference -14.26 (CI -26.55 to -1.977); session 6: -19.30 (CI -31.59 to -7.016); session 7: -13.35 (CI -25.64 to -1.067); and session 9:, -13.43 (CI -25.71 to -1.141); Fig 2A left). Time intervals between reaching trials were used as a measure of motivation. They were significantly longer in all training sessions in PLC inhibitor-treated rats as compared with vehicle-treated controls but were unaffected in PKA inhibitor-treated rats (main effect of group: F (2, 20) = 7.398, p = 0.0039, significant post-hoc Dunnett‘s tests for comparison between PLC inhibitor and control: session 3: mean difference 7.910 (CI 2.891 to 12.93); session 4: 5.970 (CI 0.9507 to 10.99); and session 6: 6.978 (CI 1.959 to 12.00); Fig 2A right). Similar results were achieved when the drugs were applied via implanted cannulas during the steepest part of the learning curve, on day 2 and 3 of skill training (30 minutes prior to training; Fig 1B). Skill acquisition was impaired in the presence of PLC- but not PKA inhibitor compared to control rats (Fig 2B). This data set revealed a significant interaction of group and time (F (12, 150) = 1.980, p = 0.0297), but post hoc tests comparing the groups individually to control were not significant (p>0.8). There were no differences between groups with respect to the time intervals between reaching trials. The inset in Fig 2B emphasizes the lack of success improvement between days 2 and 3.

Bottom Line: Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation.Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist.These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors.

View Article: PubMed Central - PubMed

Affiliation: Clinical Neurorehabilitation, Department of Neurology, University of Zurich, Zurich, Switzerland; Rehabilitation Initiative and Technology Center Zurich (RITZ), Zurich, Switzerland; Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, United States of America.

ABSTRACT
Dopaminergic neurons in the ventral tegmental area, the major midbrain nucleus projecting to the motor cortex, play a key role in motor skill learning and motor cortex synaptic plasticity. Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation. Traditionally, D1 and D2 receptor modulate adenylyl cyclase activity and cyclic adenosine monophosphate accumulation in opposite directions via different G-proteins and bidirectionally modulate protein kinase A (PKA), leading to distinct physiological and behavioral effects. Here we show that D1 and D2 receptor activity influences motor skill acquisition and long term synaptic potentiation via phospholipase C (PLC) activation in rat primary motor cortex. Learning a new forelimb reaching task is severely impaired in the presence of PLC, but not PKA-inhibitor. Similarly, long term potentiation in motor cortex, a mechanism involved in motor skill learning, is reduced when PLC is inhibited but remains unaffected by the PKA inhibitor. Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist. These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors. These findings reveal a novel and important action of dopamine in motor cortex that might be a future target for selective therapeutic interventions to support learning and recovery of movement resulting from injury and disease.

No MeSH data available.


Related in: MedlinePlus