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Derangement of Ras-guanine nucleotide-releasing Factor 1 (Ras-GRF1) and extracellular signal-regulated kinase (ERK) dependent striatal plasticity in L-DOPA-induced dyskinesia

Cerovic, Milica, Bagetta, Vincenza, Pendolino, Valentina, Ghiglieri, Veronica, Fasano, Stefania ORCID:, Morella, Ilaria ORCID:, Hardingham, Neil, Heuer, Andreas ORCID:, Papale, Alessandro ORCID:, Marchisella, Francesca, Giampà, Carmela, Calabresi, Paolo, Picconi, Barbara and Brambilla, Riccardo ORCID: 2015. Derangement of Ras-guanine nucleotide-releasing Factor 1 (Ras-GRF1) and extracellular signal-regulated kinase (ERK) dependent striatal plasticity in L-DOPA-induced dyskinesia. Biological Psychiatry 77 (2) , pp. 106-115. 10.1016/j.biopsych.2014.04.002

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords: Depotentiation; L-DOPA-induced dyskinesia; long-term potentiation (LTP); long-term depression (LTD); Ras-ERK signaling; Ras-GRF1; striatum
Additional Information: Available online 12 April 2014 PDF uploaded in accordance with publisher's policies at (accessed 13.11.15).
Publisher: Elsevier
ISSN: 0006-3223
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 1 April 2014
Last Modified: 11 Apr 2024 01:06

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