Dopamine Promotes Motor Cortex Plasticity and Motor Skill Learning via PLC Activation.
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.
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.
Mengia-Seraina
MS
Rioult-Pedotti
Clinical Neurorehabilitation, Department of Neurology, University of Zurich, Zurich, Switzerland; Rehabilitation Initiative and Technology Center Zurich (RITZ), Zurich, Switzerland.
Ana
A
Pekanovic
Clinical Neurorehabilitation, Department of Neurology, University of Zurich, Zurich, Switzerland; Rehabilitation Initiative and Technology Center Zurich (RITZ), Zurich, Switzerland.
Clement Osei
CO
Atiemo
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, United States of America.
John
J
Marshall
Clinical Neurorehabilitation, Department of Neurology, University of Zurich, Zurich, Switzerland; Rehabilitation Initiative and Technology Center Zurich (RITZ), Zurich, Switzerland; Division of Vascular Neurology and Neurorehabilitation, Department of Neurology, University Hospital Zürich, Zurich, Switzerland.
Andreas Rüdiger
AR
Luft
D000818:Animals; D004298:Dopamine / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007858:Learning / Q000187:drug effects*; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D009044:Motor Cortex / Q000187:drug effects / Q000502:physiology*; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects*; D020318:Rats, Long-Evans; D011954:Receptors, Dopamine / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D010738:Type C Phospholipases / Q000378:metabolism*
D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D011954:Receptors, Dopamine; D010738:Type C Phospholipases; D004298:Dopamine