Derangement of Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) and Extracellular Signal-Regulated Kinase (ERK) Dependent Striatal Plasticity in L-DOPA-Induced Dyskinesia

doi:10.1016/j.biopsych.2014.04.002

Biological Psychiatry

Volume 77, Issue 2, 15 January 2015, Pages 106-115

https://doi.org/10.1016/j.biopsych.2014.04.002 Get rights and content

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.

Section snippets

Methods and Materials

A detailed description of all methods and materials can be found in Supplement 1. Generation of Ras-GRF1 knockout (KO) mice has been previously described (20, 21, 22). Bac-enhanced green fluorescent protein (EGFP) mice (M4-EGFP and A2A-EGFP) were originally generated by the Gene Expression Nervous System Atlas program at Rockefeller University (www.gensat.org) (23). For lesion and LID studies, mice were injected with 6-OHDA into the right medial forebrain bundle, and AIMs were induced as

ERK Signaling Is Necessary for HFS-LTP at Corticostriatal Synapse

The Ras-ERK signaling pathway in the dorsal portion of the striatum is abnormally activated in response to both drugs of abuse and L-DOPA (15, 26). Hyperactivation of this signaling cascade may represent a key pathological factor for both drug addiction and LID, two conditions relying on abnormal DA-mediated adaptations in the basal ganglia system. In particular, we showed more recently that Ras-GRF1, a neuronal specific guanosine diphosphate/guanosine triphosphate (GDP/GTP) Ras-exchange

Discussion

The Ras-ERK signaling pathway is activated in MSNs by a combined engagement of DA and glutamate receptors, making it a suitable candidate for having a regulatory role in striatal synaptic plasticity (14, 15, 16). It is now well established that distinct chemical stimuli are able to activate ERK signaling in specific MSN subpopulations. For example, psychostimulants in intact animals and L-DOPA in denervated animals selectively activate the ERK cascade in MSNs of the direct pathway (30, 31). The

Acknowledgments and Disclosures

This paper is dedicated to the memory of Prof. Renata Zippel (1948–2011). We thank Paul Kemp for granting us laboratory space, Raffaella Tonini for critical reading the manuscript and Marianne Benoit-Marand for her initial crucial help with technical issues. The work was supported by the Michael J. Fox Foundation for Parkinson’s Research (to RB), by Parkinson’s UK (to RB), the Italian Ministry of Health (to RB, PC, and BP), the Compagnia di San Paolo (to RB and PC) and the European Community

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Ras–ERK pathway is essential for both activity-dependent striatal LTP and synaptic depotentiation. Therefore, is not surprising that the ablation of Ras protein-specific guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal activator of Ras proteins, causes a specific loss of LTP in MSNs in the direct pathway without affecting LTP in the indirect pathway resulting in LIDs in 6-OHDA-lesioned animals (Cerovic et al., 2015). The concept of a distinct pattern of abnormal bidirectional synaptic plasticity as a functional marker of PD and LIDs has been confirmed in PD patients undergoing deep brain stimulation (DBS).
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Archival ReportDerangement 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

Methods

Results

Conclusions

Section snippets

Methods and Materials

ERK Signaling Is Necessary for HFS-LTP at Corticostriatal Synapse

Discussion

Acknowledgments and Disclosures

Trends Neurosci

Neuron

Curr Opin Neurobiol

Neurotoxicology

Curr Opin Neurobiol

Curr Opin Pharmacol

Biol Psychiatry

Trends Neurosci

Neuron

Curr Opin Cell Biol

Curr Opin Genet Dev

Long-term synaptic depression in the striatum: Physiological and pharmacological characterization

J Neurosci

Long term potentiation in the striatum is unmasked by removing the voltage-dependent blockade of NMDA receptor channel

Eur J Neurosci

Unilateral dopamine denervation blocks corticostriatal LTP

J Neurophysiol

Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia

Nat Neurosci

L-DOPA treatment selectively restores spine density in dopamine receptor D2-expressing projection neurons in dyskinetic mice [published online ahead of print Jun 12]

Biol Psychiatry

Inhibition of phosphodiesterases rescues striatal long-term depression and reduces levodopa-induced dyskinesia

Brain

MAPK cascade signalling and synaptic plasticity

Nat Rev

Mitogen-activated protein kinase/extracellular regulated kinase signalling and memory stabilization: A review

Genes Brain Behav

Ras-ERK signaling in behavior: Old questions and new perspectives

Front Behav Neurosci

L-DOPA-induced dyskinesia and abnormal signaling in striatal medium spiny neurons: Focus on dopamine D1 receptor-mediated transmission

Front Behav Neurosci

Contributions of ERK signaling in the striatum to instrumental learning and performance

Behav Brain Res

Archival Report
Derangement of Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) and Extracellular Signal-Regulated Kinase (ERK) Dependent Striatal Plasticity in L-DOPA-Induced Dyskinesia