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



      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.


      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.


      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.


      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.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Calabresi P.
        • Picconi B.
        • Tozzi A.
        • Di Filippo M.
        Dopamine-mediated regulation of corticostriatal synaptic plasticity.
        Trends Neurosci. 2007; 30: 211-219
        • Kreitzer A.C.
        • Malenka R.C.
        Striatal plasticity and basal ganglia circuit function.
        Neuron. 2008; 60: 543-554
        • Surmeier D.J.
        • Plotkin J.
        • Shen W.
        Dopamine and synaptic plasticity in dorsal striatal circuits controlling action selection.
        Curr Opin Neurobiol. 2009; 19: 621-628
        • Calabresi P.
        • Maj R.
        • Pisani A.
        • Mercuri N.B.
        • Bernardi G.
        Long-term synaptic depression in the striatum: Physiological and pharmacological characterization.
        J Neurosci. 1992; 12: 4224-4233
        • Calabresi P.
        • Pisani A.
        • Mercuri N.B.
        • Bernardi G.
        Long term potentiation in the striatum is unmasked by removing the voltage-dependent blockade of NMDA receptor channel.
        Eur J Neurosci. 1992; 4: 929-935
        • Centonze D.
        • Gubellini P.
        • Picconi B.
        • Calabresi P.
        • Giacomini P.
        • Bernardi G.
        Unilateral dopamine denervation blocks corticostriatal LTP.
        J Neurophysiol. 1999; 82: 3575-3579
        • Picconi B.
        • Centonze D.
        • Hakansson K.
        • Bernardi G.
        • Greengard P.
        • Fisone G.
        • et al.
        Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia.
        Nat Neurosci. 2003; 6: 501-506
        • Suarez L.M.
        • Solis O.
        • Carames J.M.
        • Taravini I.R.
        • Solis J.M.
        • Murer M.G.
        • et al.
        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. 2013;
        • Picconi B.
        • Pisani A.
        • Barone I.
        • Bonsi P.
        • Centonze D.
        • Bernardi G.
        • et al.
        Pathological synaptic plasticity in the striatum: Implications for Parkinson’s disease.
        Neurotoxicology. 2005; 26: 779-783
        • Picconi B.
        • Bagetta V.
        • Ghiglieri V.
        • Paille V.
        • Di Filippo M.
        • Pendolino V.
        • et al.
        Inhibition of phosphodiesterases rescues striatal long-term depression and reduces levodopa-induced dyskinesia.
        Brain. 2010; 134: 375-387
        • Thomas G.M.
        • Huganir R.L.
        MAPK cascade signalling and synaptic plasticity.
        Nat Rev. 2004; 5: 173-183
        • Sweatt J.D.
        Mitogen-activated protein kinases in synaptic plasticity and memory.
        Curr Opin Neurobiol. 2004; 14: 311-317
        • Davis S.
        • Laroche S.
        Mitogen-activated protein kinase/extracellular regulated kinase signalling and memory stabilization: A review.
        Genes Brain Behav. 2006; 5: 61-72
        • Girault J.A.
        • Valjent E.
        • Caboche J.
        • Herve D.
        ERK2: A logical AND gate critical for drug-induced plasticity?.
        Curr Opin Pharmacol. 2007; 7: 77-85
        • Fasano S.
        • Brambilla R.
        Ras-ERK signaling in behavior: Old questions and new perspectives.
        Front Behav Neurosci. 2011; 5: 79
        • Feyder M.
        • Bonito-Oliva A.
        • Fisone G.
        L-DOPA-induced dyskinesia and abnormal signaling in striatal medium spiny neurons: Focus on dopamine D1 receptor-mediated transmission.
        Front Behav Neurosci. 2011; 5: 71
        • Shiflett M.W.
        • Balleine B.W.
        Contributions of ERK signaling in the striatum to instrumental learning and performance.
        Behav Brain Res. 2010; 218: 240-247
        • Calabresi P.
        • Gubellini P.
        • Picconi B.
        • Centonze D.
        • Pisani A.
        • Bonsi P.
        • et al.
        Inhibition of mitochondrial complex II induces a long-term potentiation of NMDA-mediated synaptic excitation in the striatum requiring endogenous dopamine.
        J Neurosci. 2001; 21: 5110-5120
        • Xie G.Q.
        • Wang S.J.
        • Li J.
        • Cui S.Z.
        • Zhou R.
        • Chen L.
        • et al.
        Ethanol attenuates the HFS-induced, ERK-mediated LTP in a dose-dependent manner in rat striatum.
        Alcohol Clin Exp Res. 2009; 33: 121-128
        • Brambilla R.
        • Gnesutta N.
        • Minichiello L.
        • White G.
        • Roylance A.J.
        • Herron C.E.
        • et al.
        A role for the Ras signalling pathway in synaptic transmission and long-term memory.
        Nature. 1997; 390: 281-286
        • Fasano S.
        • D’Antoni A.
        • Orban P.C.
        • Valjent E.
        • Putignano E.
        • Vara H.
        • et al.
        Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) controls activation of extracellular signal-regulated kinase (ERK) signaling in the striatum and long-term behavioral responses to cocaine.
        Biol Psychiatry. 2009; 66: 758-768
        • Fasano S.
        • Bezard E.
        • D’Antoni A.
        • Francardo V.
        • Indrigo M.
        • Qin L.
        • et al.
        Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia.
        Proc Natl Acad Sci U S A. 2010; 107: 21824-21829
        • Gong S.
        • Zheng C.
        • Doughty M.L.
        • Losos K.
        • Didkovsky N.
        • Schambra U.B.
        • et al.
        A gene expression atlas of the central nervous system based on bacterial artificial chromosomes.
        Nature. 2003; 425: 917-925
        • Nazzaro C.
        • Greco B.
        • Cerovic M.
        • Baxter P.
        • Rubino T.
        • Trusel M.
        • et al.
        SK channel modulation rescues striatal plasticity and control over habit in cannabinoid tolerance.
        Nat Neurosci. 2012; 15: 284-293
        • Orellana D.
        • Morella I.M.
        • Indrigo M.
        • Papale A.
        • Brambilla R.
        The ERK cascade in neuronal cell signaling.
        in: Mukai H. Protein Kinase Technologies. Springer, New York2012: 133-152
        • Murer M.G.
        • Moratalla R.
        Striatal signaling in L-DOPA-induced dyskinesia: Common mechanisms with drug abuse and long term memory involving D1 dopamine receptor stimulation.
        Front Neuroanat. 2011; 5: 51
        • Calabresi P.
        • Di Filippo M.
        • Ghiglieri V.
        • Picconi B.
        Molecular mechanisms underlying levodopa-induced dyskinesia.
        Mov Disord. 2008; 23: S570-S579
        • Cenci M.A.
        Dopamine dysregulation of movement control in L-DOPA-induced dyskinesia.
        Trends Neurosci. 2007; 30: 236-243
        • Jenner P.
        Molecular mechanisms of L-DOPA-induced dyskinesia.
        Nat Rev. 2008; 9: 665-677
        • Bertran-Gonzalez J.
        • Bosch C.
        • Maroteaux M.
        • Matamales M.
        • Herve D.
        • Valjent E.
        • et al.
        Opposing patterns of signaling activation in dopamine D1 and D2 receptor-expressing striatal neurons in response to cocaine and haloperidol.
        J Neurosci. 2008; 28: 5671-5685
        • Santini E.
        • Alcacer C.
        • Cacciatore S.
        • Heiman M.
        • Herve D.
        • Greengard P.
        • et al.
        L-DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice.
        J Neurochem. 2009; 108: 621-633
        • Kreitzer A.C.
        • Malenka R.C.
        Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson’s disease models.
        Nature. 2007; 445: 643-647
        • Shen W.
        • Flajolet M.
        • Greengard P.
        • Surmeier D.J.
        Dichotomous dopaminergic control of striatal synaptic plasticity.
        Science (New York, NY). 2008; 321: 848-851
        • Malenka R.C.
        • Bear M.F.
        LTP and LTD: An embarrassment of riches.
        Neuron. 2004; 44: 5-21
        • Petersen C.C.
        • Malenka R.C.
        • Nicoll R.A.
        • Hopfield J.J.
        All-or-none potentiation at CA3-CA1 synapses.
        Proc Natl Acad Sci U S A. 1998; 95: 4732-4737
        • O’Connor D.H.
        • Wittenberg G.M.
        • Wang S.S.
        Graded bidirectional synaptic plasticity is composed of switch-like unitary events.
        Proc Natl Acad Sci U S A. 2005; 102: 9679-9684
        • Bhalla U.S.
        • Iyengar R.
        Emergent properties of networks of biological signaling pathways.
        Science (New York, NY). 1999; 283: 381-387
        • Ferrell Jr, J.E.
        Self-perpetuating states in signal transduction: Positive feedback, double-negative feedback and bistability.
        Curr Opin Cell Biol. 2002; 14: 140-148
        • Shankaran H.
        • Wiley H.S.
        Oscillatory dynamics of the extracellular signal-regulated kinase pathway.
        Curr Opin Genet Dev. 2010; 20: 650-655
        • Stern E.A.
        • Kincaid A.E.
        • Wilson C.J.
        Spontaneous subthreshold membrane potential fluctuations and action potential variability of rat corticostriatal and striatal neurons in vivo.
        J Neurophysiol. 1997; 77: 1697-1715
        • Wilson C.J.
        • Kawaguchi Y.
        The origins of two-state spontaneous membrane potential fluctuations of neostriatal spiny neurons.
        J Neurosci. 1996; 16: 2397-2410
        • de la Fuente-Fernandez R.
        • Sossi V.
        • Huang Z.
        • Furtado S.
        • Lu J.Q.
        • Calne D.B.
        • et al.
        Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson’s disease: Implications for dyskinesias.
        Brain. 2004; 127: 2747-2754
        • Stocchi F.
        • Jenner P.
        • Obeso J.A.
        When do levodopa motor fluctuations first appear in Parkinson’s disease?.
        Eur Neurol. 2010; 63: 257-266
        • Porras G.
        • De Deurwaerdere P.
        • Li Q.
        • Marti M.
        • Morgenstern R.
        • Sohr R.
        • et al.
        L-dopa-induced dyskinesia: Beyond an excessive dopamine tone in the striatum.
        Sci Rep. 2014; 4: 3730