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

BACKGROUND Ras-extracellular signal-regulated kinase (Ras-ERK) signaling is central to the molecular machinery underlying cognitive functions. In the striatum, ERK1/2 kinases are co-activated by glutamate and dopamine D1/5 receptors, but the mechanisms providing such signaling integration are still unknown. The Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal specific activator of Ras-ERK signaling, is a likely candidate for coupling these neurotransmitter signals to ERK kinases in the striatonigral medium spiny neurons (MSN) and for modulating behavioral responses to drug abuse such as cocaine. METHODS We used genetically modified mouse mutants for Ras-GRF1 as a source of primary MSN cultures and organotypic slices, to perform both immunoblot and immunofluorescence studies in response to glutamate and dopamine receptor agonists. Mice were also subjected to behavioral and immunohistochemical investigations upon treatment with cocaine. RESULTS Phosphorylation of ERK1/2 in response to glutamate, dopamine D1 agonist, or both stimuli simultaneously is impaired in Ras-GRF1-deficient striatal cells and organotypic slices of the striatonigral MSN compartment. Consistently, behavioral responses to cocaine are also affected in mice deficient for Ras-GRF1 or overexpressing it. Both locomotor sensitization and conditioned place preference are significantly attenuated in Ras-GRF1-deficient mice, whereas a robust facilitation is observed in overexpressing transgenic animals. Finally, we found corresponding changes in ERK1/2 activation and in accumulation of FosB/DeltaFosB, a well-characterized marker for long-term responses to cocaine, in MSN from these animals. CONCLUSIONS These results strongly implicate Ras-GRF1 in the integration of the two main neurotransmitter inputs to the striatum and in the maladaptive modulation of striatal networks in response to cocaine.

[1]  Angus C Nairn,et al.  DARPP-32: an integrator of neurotransmission. , 2004, Annual review of pharmacology and toxicology.

[2]  Pei-Chun Chen,et al.  Dual alteration of limbic dopamine D1 receptor‐mediated signalling and the Akt/GSK3 pathway in dopamine D3 receptor mutants during the development of methamphetamine sensitization , 2007, Journal of neurochemistry.

[3]  S. Davis,et al.  Mitogen‐activated protein kinase/extracellular regulated kinase signalling and memory stabilization: a review , 2006, Genes, brain, and behavior.

[4]  A M Graybiel,et al.  A family of cAMP-binding proteins that directly activate Rap1. , 1998, Science.

[5]  R. Andrade,et al.  Phosphorylation of the Ras-GRF1 Exchange Factor at Ser916/898 Reveals Activation of Ras Signaling in the Cerebral Cortex* , 2003, The Journal of Biological Chemistry.

[6]  J. Norum,et al.  Endogenous expression and protein kinase A‐dependent phosphorylation of the guanine nucleotide exchange factor Ras‐GRF1 in human embryonic kidney 293 cells , 2005, The FEBS journal.

[7]  Ying Xia,et al.  Cocaine-Induced Intracellular Signaling and Gene Expression Are Oppositely Regulated by the Dopamine D1 and D3 Receptors , 2004, The Journal of Neuroscience.

[8]  Paul Greengard,et al.  The Neurobiology of Dopamine Signaling , 2004 .

[9]  J. Stone,et al.  RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. , 1998, Science.

[10]  J. Girault,et al.  Role of the ERK pathway in psychostimulant-induced locomotor sensitization , 2006, BMC Neuroscience.

[11]  S. Grewal,et al.  Extracellular-signal-regulated kinase signalling in neurons , 1999, Current Opinion in Neurobiology.

[12]  Y. Shaham,et al.  Role of ERK in cocaine addiction , 2006, Trends in Neurosciences.

[13]  E. Lo,et al.  Developmentally regulated role for Ras‐GRFs in coupling NMDA glutamate receptors to Ras, Erk and CREB , 2004, The EMBO journal.

[14]  L. Feig,et al.  Age-dependent Participation of Ras-GRF Proteins in Coupling Calcium-permeable AMPA Glutamate Receptors to Ras/Erk Signaling in Cortical Neurons* , 2006, Journal of Biological Chemistry.

[15]  S. Hyman,et al.  Metabotropic Glutamate Receptors and Dopamine Receptors Cooperate to Enhance Extracellular Signal-Regulated Kinase Phosphorylation in Striatal Neurons , 2005, The Journal of Neuroscience.

[16]  M. Kelz,et al.  &Dgr;FosB: a molecular switch underlying long-term neural plasticity , 2000, Current opinion in neurology.

[17]  I. Macara,et al.  Phosphorylation-dependent activation of the Ras-GRF/CDC25Mm exchange factor by muscarinic receptors and G-protein βγ subunits , 1996, Nature.

[18]  E. Martegani,et al.  Involvement of CDC25Mm/Ras-GRF1-Dependent Signaling in the Control of Neuronal Excitability , 2001, Molecular and Cellular Neuroscience.

[19]  J. Girault,et al.  Parsing Molecular and Behavioral Effects of Cocaine in Mitogen- and Stress-Activated Protein Kinase-1-Deficient Mice , 2005, The Journal of Neuroscience.

[20]  Todor V. Gerdjikov,et al.  Place preference induced by nucleus accumbens amphetamine is impaired by antagonists of ERK or p38 MAP kinases in rats. , 2004, Behavioral neuroscience.

[21]  J. D. Sweatt,et al.  Epigenetic mechanisms in memory formation , 2010, International Journal of Developmental Neuroscience.

[22]  Peter J. Cullen,et al.  Integration of calcium and RAS signalling , 2002, Nature Reviews Molecular Cell Biology.

[23]  J. Penney,et al.  Expression of NMDA glutamate receptor subunit mRNAs in neurochemically identified projection and interneurons in the striatum of the rat. , 1999, Brain research. Molecular brain research.

[24]  P. Orban,et al.  Two ENU-induced mutations in Rasgrf1 and early mouse growth retardation , 2003, Mammalian Genome.

[25]  P. Chapman,et al.  Is the Ras-MAPK signalling pathway necessary for long-term memory formation? , 1999, Trends in Neurosciences.

[26]  E. Martegani,et al.  The Ras Guanine nucleotide Exchange Factor CDC25Mm is present at the synaptic junction. , 1997, Experimental cell research.

[27]  K. Berridge,et al.  The neural basis of drug craving: An incentive-sensitization theory of addiction , 1993, Brain Research Reviews.

[28]  A. Graybiel,et al.  A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Anirvan Ghosh,et al.  Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF , 1995, Nature.

[30]  Burton S. Rosner,et al.  Neuropharmacology , 1958, Nature.

[31]  B. Prasad,et al.  Neurotrophin-3 Contributes to the Initiation of Behavioral Sensitization to Cocaine by Activating the Ras/Mitogen-Activated Protein Kinase Signal Transduction Cascade , 1999, The Journal of Neuroscience.

[32]  J. Pouysségur,et al.  Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. , 2003, Biochemical pharmacology.

[33]  Denis Hervé,et al.  ERK2: a logical AND gate critical for drug-induced plasticity? , 2007, Current opinion in pharmacology.

[34]  E. Nestler,et al.  Molecular Neurobiology of Drug Addiction , 1994, Neuropsychopharmacology.

[35]  J. Pouysségur,et al.  Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. , 2002, European journal of biochemistry.

[36]  T. Robinson,et al.  Knockout of ERK1 Enhances Cocaine-Evoked Immediate Early Gene Expression and Behavioral Plasticity , 2006, Neuropsychopharmacology.

[37]  Bert Sakmann,et al.  Heteromeric NMDA Receptors: Molecular and Functional Distinction of Subtypes , 1992, Science.

[38]  Rony Seger,et al.  The MEK/ERK cascade: from signaling specificity to diverse functions. , 2007, Biochimica et biophysica acta.

[39]  Alcino J. Silva,et al.  Hippocampus-dependent learning and memory is impaired in mice lacking the Ras-guanine-nucleotide releasing factor 1 (Ras-GRF1) , 2001, Neuropharmacology.

[40]  L. Kaczmarek,et al.  Extracellular signal‐regulated kinases (ERKs) modulate cocaine‐induced gene expression in the mouse amygdala , 2005, The European journal of neuroscience.

[41]  B. Sakmann,et al.  Developmental and regional expression in the rat brain and functional properties of four NMDA receptors , 1994, Neuron.

[42]  Shaomin Li,et al.  The Environment versus Genetics in Controlling the Contribution of MAP Kinases to Synaptic Plasticity , 2006, Current Biology.

[43]  M. Barbacid,et al.  RAS oncogenes: the first 30 years , 2003, Nature Reviews Cancer.

[44]  B. Kholodenko.  Cell-signalling dynamics in time and space , 2006, Nature Reviews Molecular Cell Biology.

[45]  T. Robbins,et al.  Neural systems of reinforcement for drug addiction: from actions to habits to compulsion , 2005, Nature Neuroscience.

[46]  Zippel Renata,et al.  Ras-GRF, the activator of Ras, is expressed preferentially in mature neurons of the central nervous system , 1997 .

[47]  M. Besson,et al.  Involvement of the Extracellular Signal-Regulated Kinase Cascade for Cocaine-Rewarding Properties , 2000, The Journal of Neuroscience.

[48]  I. Macara,et al.  Activation of the Ras-GRF/CDC25Mm exchange factor by lysophosphatidic acid. , 1999, Cellular signalling.

[49]  E. Borrelli,et al.  Absence of opiate rewarding effects in mice lacking dopamine D2 receptors , 1997, Nature.

[50]  Paul Greengard,et al.  The role of DARPP-32 in the actions of drugs of abuse , 2004, Neuropharmacology.

[51]  W. Kolch.  Coordinating ERK/MAPK signalling through scaffolds and inhibitors , 2005, Nature Reviews Molecular Cell Biology.

[52]  Jesus Bertran-Gonzalez,et al.  Inhibition of ERK pathway or protein synthesis during reexposure to drugs of abuse erases previously learned place preference. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[53]  E. Martegani,et al.  The brain specific Ras exchange factor CDC25 Mm: modulation of its activity through Gi-protein-mediated signals. , 1996, Oncogene.

[54]  D. Surmeier,et al.  Multiplicity of glutamate receptor subunits in single striatal neurons: an RNA amplification study. , 1996, Molecular pharmacology.

[55]  L. Raymond,et al.  Role of NR2B-type NMDA receptors in selective neurodegeneration in Huntington disease , 2003, Neurobiology of Aging.

[56]  R. Malenka,et al.  Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens. , 2000, Annual review of neuroscience.

[57]  Eric J. Nestler,et al.  Epigenetic regulation in psychiatric disorders , 2007, Nature Reviews Neuroscience.

[58]  Victor V Lobanenkov,et al.  Rasgrf1 Imprinting Is Regulated by a CTCF-Dependent Methylation-Sensitive Enhancer Blocker , 2005, Molecular and Cellular Biology.

[59]  E. Valjent,et al.  Mitogen-activated protein kinase/extracellular signal-regulated kinase induced gene regulation in brain: a molecular substrate for learning and memory? , 2001, Molecular neurobiology.

[60]  J. Girault,et al.  DARPP-32 is a robust integrator of dopamine and glutamate signals , 2006 .

[61]  S. Grant,et al.  A role for the Ras signalling pathway in synaptic transmission and long-term memory , 1997, Nature.

[62]  K. Rosenblum,et al.  Co‐application of NMDA and dopamine‐induced rapid translation of RSK2 in the mature hippocampus , 2007, Journal of neurochemistry.

[63]  Shaomin Li,et al.  Distinct Roles for Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) and Ras-GRF2 in the Induction of Long-Term Potentiation and Long-Term Depression , 2006, The Journal of Neuroscience.

[64]  L. Naldini,et al.  ERK1 and ERK2 mitogen-activated protein kinases affect Ras-dependent cell signaling differentially , 2006, Journal of biology.

[65]  S. Fasano,et al.  Cellular mechanisms of striatum-dependent behavioral plasticity and drug addiction. , 2002, Current molecular medicine.

[66]  David P Wolfer,et al.  Knockout of ERK1 MAP Kinase Enhances Synaptic Plasticity in the Striatum and Facilitates Striatal-Mediated Learning and Memory , 2002, Neuron.

[67]  R. Huganir,et al.  MAPK cascade signalling and synaptic plasticity , 2004, Nature Reviews Neuroscience.

[68]  Yehezkel Ben-Ari,et al.  The NMDA Receptor Is Coupled to the ERK Pathway by a Direct Interaction between NR2B and RasGRF1 , 2003, Neuron.

[69]  J. Sweatt,et al.  Mitogen-activated protein kinases in synaptic plasticity and memory , 2004, Current Opinion in Neurobiology.

[70]  E. Valjent,et al.  Mitogen-activated protein kinase/extracellular signal-regulated kinase induced gene regulation in brain , 2001, Molecular Neurobiology.

[71]  J. Girault,et al.  Opposing Patterns of Signaling Activation in Dopamine D1 and D2 Receptor-Expressing Striatal Neurons in Response to Cocaine and Haloperidol , 2008, The Journal of Neuroscience.

[72]  Y. Shaham,et al.  Central amygdala ERK signaling pathway is critical to incubation of cocaine craving , 2005, Nature Neuroscience.

[73]  L. Raymond,et al.  Subtype-Dependence of NMDA Receptor Channel Open Probability , 1999, The Journal of Neuroscience.

[74]  S. Heinemann,et al.  Cloned glutamate receptors. , 1994, Annual review of neuroscience.

[75]  T. Robinson,et al.  Amphetamine‐evoked c‐fos mRNA expression in the caudate‐putamen: the effects of DA and NMDA receptor antagonists vary as a function of neuronal phenotype and environmental context , 2003, Journal of neurochemistry.

[76]  A. Kelley.  Memory and Addiction Shared Neural Circuitry and Molecular Mechanisms , 2004, Neuron.

[77]  J. Marshall,et al.  Molecular Substrates for Retrieval and Reconsolidation of Cocaine-Associated Contextual Memory , 2005, Neuron.

[78]  E. Nestler,et al.  Molecular basis of long-term plasticity underlying addiction , 2001, Nature Reviews Neuroscience.

[79]  J. Rivas,et al.  Laser microdissection and microarray analysis of the hippocampus of Ras-GRF1 knockout mice reveals gene expression changes affecting signal transduction pathways related to memory and learning , 2007, Neuroscience.

[80]  S. Hyman,et al.  Addiction, Dopamine, and the Molecular Mechanisms of Memory , 2000, Neuron.

[81]  R. Buchsbaum,et al.  The N-terminal pleckstrin, coiled-coil, and IQ domains of the exchange factor Ras-GRF act cooperatively to facilitate activation by calcium , 1996, Molecular and cellular biology.

[82]  S. Hyman,et al.  Neural mechanisms of addiction: the role of reward-related learning and memory. , 2006, Annual review of neuroscience.

[83]  R. Brambilla,et al.  CDC25Mm/Ras‐GRF1 regulates both Ras and Rac signaling pathways , 1999, FEBS letters.

[84]  Q. Tang,et al.  Regulation of MAPK/ERK phosphorylation via ionotropic glutamate receptors in cultured rat striatal neurons , 2004, The European journal of neuroscience.

[85]  Angus C Nairn,et al.  Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[86]  Q. Tang,et al.  The Scaffold Protein Homer1b/c Links Metabotropic Glutamate Receptor 5 to Extracellular Signal-Regulated Protein Kinase Cascades in Neurons , 2005, The Journal of Neuroscience.

[87]  G. Landwehrmeyer,et al.  NMDA receptor subunit mRNA expression by projection neurons and interneurons in rat striatum , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[88]  J. Girault,et al.  Addictive and non‐addictive drugs induce distinct and specific patterns of ERK activation in mouse brain , 2004, The European journal of neuroscience.

[89]  Mary B. Kennedy,et al.  Integration of biochemical signalling in spines , 2005, Nature Reviews Neuroscience.

[90]  J. Sweatt,et al.  Molecular psychology: roles for the ERK MAP kinase cascade in memory. , 2002, Annual review of pharmacology and toxicology.

[91]  Q. Tang,et al.  A Novel Ca2+-Independent Signaling Pathway to Extracellular Signal-Regulated Protein Kinase by Coactivation of NMDA Receptors and Metabotropic Glutamate Receptor 5 in Neurons , 2004, The Journal of Neuroscience.

[92]  I. Macara,et al.  Phosphorylation-dependent activation of the Ras-GRF/CDC25Mm exchange factor by muscarinic receptors and G-protein beta gamma subunits. , 1996, Nature.