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

Abstract

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.

• Authors: Milica Cerovic, Vincenza Bagetta, Valentina Pendolino, Veronica Ghiglieri, Stefania Fasano, Ilaria Morella, Neil Hardingham, Andreas Heuer, Alessandro Papale, Francesca Marchisella, Carmela Giampà, Paolo Calabresi, Barbara Picconi, Riccardo Brambilla
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 77 Issue 2 Pg. 106-15 (Jan 15 2015) ISSN: 1873-2402 [Electronic] United States
• PMID: 24844602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antiparkinson Agents
• Butadienes
• Nitriles
• Protein Kinase Inhibitors
• Rasgrf1 protein, mouse
• U 0126
• ras-GRF1
• Levodopa
• Oxidopamine
• Extracellular Signal-Regulated MAP Kinases
• Dopamine

Topics

• Animals
• Antiparkinson Agents (toxicity)
• Butadienes (pharmacology)
• Cerebral Cortex (drug effects, physiopathology)
• Corpus Striatum (drug effects, physiopathology)
• Dopamine (metabolism)
• Dyskinesia, Drug-Induced (physiopathology)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Levodopa (toxicity)
• Mice, Knockout
• Neuronal Plasticity (drug effects, physiology)
• Neurons (drug effects, physiology)
• Nitriles (pharmacology)
• Oxidopamine
• Parkinsonian Disorders (drug therapy, physiopathology)
• Protein Kinase Inhibitors (pharmacology)
• Tissue Culture Techniques
• ras-GRF1 (genetics, metabolism)