Derangement of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and extracellular signal-regulated kinase (ERK) dependent striatal plasticity in L-DOPA-induced dyskinesia.
BACKGROUND
Bidirectional long-term plasticity at the corticostriatal synapse has been proposed as a central cellular mechanism governing dopamine-mediated behavioral adaptations in the basal ganglia system. Balanced activity of medium spiny neurons (MSNs) in the direct and the indirect pathways is essential for normal striatal function. This balance is disrupted in Parkinson's disease and in l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID), a common motor complication of current pharmacotherapy of Parkinson's disease.


METHODS
Electrophysiological recordings were performed in mouse cortico-striatal slice preparation. Synaptic plasticity, such as long-term potentiation (LTP) and depotentiation, was investigated. Specific pharmacological inhibitors or genetic manipulations were used to modulate the Ras-extracellular signal-regulated kinase (Ras-ERK) pathway, a signal transduction cascade implicated in behavioral plasticity, and synaptic activity in different subpopulations of striatal neurons was measured.


RESULTS
We found that the Ras-ERK pathway, is not only essential for long-term potentiation induced with a high frequency stimulation protocol (HFS-LTP) in the dorsal striatum, but also for its reversal, synaptic depotentiation. Ablation of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal activator of Ras proteins, causes a specific loss of HFS-LTP in the medium spiny neurons in the direct pathway without affecting LTP in the indirect pathway. Analysis of LTP in animals with unilateral 6-hydroxydopamine lesions (6-OHDA) rendered dyskinetic with chronic L-DOPA treatment reveals a complex, Ras-GRF1 and pathway-independent, apparently stochastic involvement of ERK.


CONCLUSIONS
These data not only demonstrate a central role for Ras-ERK signaling in striatal LTP, depotentiation, and LTP restored after L-DOPA treatment but also disclose multifaceted synaptic adaptations occurring in response to dopaminergic denervation and pulsatile administration of L-DOPA.
School of Biosciences, Cardiff University, Cardiff, United Kingdom; Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milano.
Milica
M
Cerovic
Fondazione Santa Lucia, IRCCS, Rome.
Vincenza
V
Bagetta
Fondazione Santa Lucia, IRCCS, Rome.
Valentina
V
Pendolino
Fondazione Santa Lucia, IRCCS, Rome.
Veronica
V
Ghiglieri
Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milano.
Stefania
S
Fasano
Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milano.
Ilaria
I
Morella
School of Biosciences, Cardiff University, Cardiff, United Kingdom.
Neil
N
Hardingham
School of Biosciences, Cardiff University, Cardiff, United Kingdom.
Andreas
A
Heuer
Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milano.
Alessandro
A
Papale
Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milano.
Francesca
F
Marchisella
Fondazione Santa Lucia, IRCCS, Rome.
Carmela
C
Giampà
Fondazione Santa Lucia, IRCCS, Rome; Clinica Neurologica, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
Paolo
P
Calabresi
Fondazione Santa Lucia, IRCCS, Rome.
Barbara
B
Picconi
Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milano. Electronic address: brambilla.riccardo@hsr.it.
Riccardo
R
Brambilla
D000818:Animals; D000978:Antiparkinson Agents / Q000633:toxicity; D002070:Butadienes / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007980:Levodopa / Q000633:toxicity; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D046509:Tissue Culture Techniques; D020666:ras-GRF1 / Q000235:genetics / Q000378:metabolism*
D000978:Antiparkinson Agents; D002070:Butadienes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C513037:Rasgrf1 protein, mouse; C113580:U 0126; D020666:ras-GRF1; D007980:Levodopa; D016627:Oxidopamine; D048049:Extracellular Signal-Regulated MAP Kinases; D004298:Dopamine
Depotentiation; L-DOPA-induced dyskinesia; Long-term depression (LTD); Long-term potentiation (LTP); Ras-ERK signaling; Ras-GRF1; Striatum