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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

Activation of intracellular PLC pathway rescues the LTP impairment caused by DA receptor block.(a) Maximum synaptic strength of horizontal layer II/III connections, measured by saturating LTP with multiple attempts of TBS (arrows) in raclopride (D2antag) co-administered with m-3m3fbs (PLCactivator, red) resulted in normal amounts of LTP (left). m-3m3fbs alone did not affect LTP saturation (green). The histogram (right) illustrates LTP saturation for control condition (grey), PLC agonist (green), PLC antagonist (blue), D2 antagonist (yellow). D1 and D2 antagonist co-applied with the PLC agonist (red) illustrates the rescue of D1 and D2 block. (b) FP amplitudes were not affected by co-administration of D2 antagonist and PLC agonist or by PLC agonist alone (left). The histogram (right) illustrates group data of synaptic strength for all the different conditions (color code as in a). Values are calculated relative to the baseline recordings before drug application.
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pone.0124986.g005: Activation of intracellular PLC pathway rescues the LTP impairment caused by DA receptor block.(a) Maximum synaptic strength of horizontal layer II/III connections, measured by saturating LTP with multiple attempts of TBS (arrows) in raclopride (D2antag) co-administered with m-3m3fbs (PLCactivator, red) resulted in normal amounts of LTP (left). m-3m3fbs alone did not affect LTP saturation (green). The histogram (right) illustrates LTP saturation for control condition (grey), PLC agonist (green), PLC antagonist (blue), D2 antagonist (yellow). D1 and D2 antagonist co-applied with the PLC agonist (red) illustrates the rescue of D1 and D2 block. (b) FP amplitudes were not affected by co-administration of D2 antagonist and PLC agonist or by PLC agonist alone (left). The histogram (right) illustrates group data of synaptic strength for all the different conditions (color code as in a). Values are calculated relative to the baseline recordings before drug application.

Mentions: We further examined whether activation of the PLC signaling pathway can rescue DA antagonist-induced LTP impairment. Synaptic strength and plasticity were determined in M1 intracortical connections before and after co-application of D1 or D2 receptor antagonist together with the PLC agonist. Saturating LTP by multiple attempts of TBS in the presence of either D1 antagonist SCH23390 plus PLC agonist m-3m3fbs or D2 antagonist raclopride plus m-3m3fbs resulted in levels of LTP (154.4±12.8, N = 4 and 162.9±9.82%, N = 11 respectively; Fig 5A left) comparable to controls (160.1±8.34%, N = 7, P = 0.35 and p = 0.85 respectively; Fig 2C), and the m-3m3fbs alone (150.3±9.81%, N = 5, p = 0.42 and p = 0.68 respectively). Thus, activation of the PLC pathway rescues LTP impairment resulting from D1 or D2 receptor blockade. The histogram (Fig 5A right) emphasizes a major role of DA induced intracellular PLC activation in M1 synaptic plasticity. Baseline synaptic transmission was not affected by D1 antagonist SCH23390, D2 antagonist raclopride and PLC agonist m-3m3fbs alone [15], or m-3m3fbs co-administered with either SCH23390 or raclopride (Fig 5B left). The extracellular FPs remained unchanged in shape and amplitude. The histogram in Fig 5B (right) illustrates drug effects as relative change to control condition (before drug application) (PLC agonist: 1.03±0.113, N = 7, P = 0.85; PLC antagonist: 1.01±0.07, N = 9, P = 0.96; D2 antagonist: 0.995±0.061, N = 10, P = 0.95; D1 antagonist & PLC agonist: 0.99±0.11, N = 4, P = 0.60: D2 antagonist & PLC agonist: 1.01±0.065, N = 13, P = 0.96).


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)

Activation of intracellular PLC pathway rescues the LTP impairment caused by DA receptor block.(a) Maximum synaptic strength of horizontal layer II/III connections, measured by saturating LTP with multiple attempts of TBS (arrows) in raclopride (D2antag) co-administered with m-3m3fbs (PLCactivator, red) resulted in normal amounts of LTP (left). m-3m3fbs alone did not affect LTP saturation (green). The histogram (right) illustrates LTP saturation for control condition (grey), PLC agonist (green), PLC antagonist (blue), D2 antagonist (yellow). D1 and D2 antagonist co-applied with the PLC agonist (red) illustrates the rescue of D1 and D2 block. (b) FP amplitudes were not affected by co-administration of D2 antagonist and PLC agonist or by PLC agonist alone (left). The histogram (right) illustrates group data of synaptic strength for all the different conditions (color code as in a). Values are calculated relative to the baseline recordings before drug application.
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Related In: Results  -  Collection

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pone.0124986.g005: Activation of intracellular PLC pathway rescues the LTP impairment caused by DA receptor block.(a) Maximum synaptic strength of horizontal layer II/III connections, measured by saturating LTP with multiple attempts of TBS (arrows) in raclopride (D2antag) co-administered with m-3m3fbs (PLCactivator, red) resulted in normal amounts of LTP (left). m-3m3fbs alone did not affect LTP saturation (green). The histogram (right) illustrates LTP saturation for control condition (grey), PLC agonist (green), PLC antagonist (blue), D2 antagonist (yellow). D1 and D2 antagonist co-applied with the PLC agonist (red) illustrates the rescue of D1 and D2 block. (b) FP amplitudes were not affected by co-administration of D2 antagonist and PLC agonist or by PLC agonist alone (left). The histogram (right) illustrates group data of synaptic strength for all the different conditions (color code as in a). Values are calculated relative to the baseline recordings before drug application.
Mentions: We further examined whether activation of the PLC signaling pathway can rescue DA antagonist-induced LTP impairment. Synaptic strength and plasticity were determined in M1 intracortical connections before and after co-application of D1 or D2 receptor antagonist together with the PLC agonist. Saturating LTP by multiple attempts of TBS in the presence of either D1 antagonist SCH23390 plus PLC agonist m-3m3fbs or D2 antagonist raclopride plus m-3m3fbs resulted in levels of LTP (154.4±12.8, N = 4 and 162.9±9.82%, N = 11 respectively; Fig 5A left) comparable to controls (160.1±8.34%, N = 7, P = 0.35 and p = 0.85 respectively; Fig 2C), and the m-3m3fbs alone (150.3±9.81%, N = 5, p = 0.42 and p = 0.68 respectively). Thus, activation of the PLC pathway rescues LTP impairment resulting from D1 or D2 receptor blockade. The histogram (Fig 5A right) emphasizes a major role of DA induced intracellular PLC activation in M1 synaptic plasticity. Baseline synaptic transmission was not affected by D1 antagonist SCH23390, D2 antagonist raclopride and PLC agonist m-3m3fbs alone [15], or m-3m3fbs co-administered with either SCH23390 or raclopride (Fig 5B left). The extracellular FPs remained unchanged in shape and amplitude. The histogram in Fig 5B (right) illustrates drug effects as relative change to control condition (before drug application) (PLC agonist: 1.03±0.113, N = 7, P = 0.85; PLC antagonist: 1.01±0.07, N = 9, P = 0.96; D2 antagonist: 0.995±0.061, N = 10, P = 0.95; D1 antagonist & PLC agonist: 0.99±0.11, N = 4, P = 0.60: D2 antagonist & PLC agonist: 1.01±0.065, N = 13, P = 0.96).

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