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ABSTRACT: Activation of the extracellular signal-regulated kinase (ERK) signaling pathway in the striatum is crucial for molecular adaptations and long-term behavioral alterations induced by cocaine. In response to cocaine, ERK controls the phosphorylation levels of both mitogen and stress-activated protein kinase 1 (MSK-1), a nuclear kinase involved in histone H3 (Ser10) and cAMP response element binding protein phosphorylation, and Elk-1, a transcription factor involved in serum response element (SRE)-driven gene regulations. We recently characterized the phenotype of msk-1 knock-out mice in response to cocaine. Herein, we wanted to address the role of Elk-1 phosphorylation in cocaine-induced molecular, morphological, and behavioral responses. We used a cell-penetrating peptide, named TAT-DEF-Elk-1 (TDE), which corresponds to the DEF docking domain of Elk-1 toward ERK and inhibits Elk-1 phosphorylation induced by ERKs without modifying ERK or MSK-1 in vitro. The peptide was injected in vivo before cocaine administration in mice. Immunocytochemical, molecular, morphological, and behavioral studies were performed. The TDE inhibited Elk-1 and H3 (Ser10) phosphorylation induced by cocaine, sparing ERK and MSK-1 activation. Consequently, TDE altered cocaine-induced regulation of genes bearing SRE site(s) in their promoters, including c-fos, zif268, ΔFosB, and arc/arg3.1 (activity-regulated cytoskeleton-associated protein). In a chronic cocaine administration paradigm, TDE reversed cocaine-induced increase in dendritic spine density. Finally, the TDE delayed the establishment of cocaine-induced psychomotor sensitization and conditioned-place preference. We conclude that Elk-1 phosphorylation downstream from ERK is a key molecular event involved in long-term neuronal and behavioral adaptations to cocaine.
Journal of Neuroscience 10/2011; 31(40):14296-307. · 7.11 Impact Factor
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Jean-Michel Peyrin,
Bérangère Deleglise,
Laure Saias,
Maéva Vignes,
Paul Gougis,
Sebastien Magnifico,
Sandrine Betuing,
Mathéa Pietri, Jocelyne Caboche,
Peter Vanhoutte,
Jean-Louis Viovy,
Bernard Brugg
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ABSTRACT: Various experimental models are used to study brain development and degeneration. They range from whole animal models, which preserve anatomical structures but strongly limit investigations at the cellular level, to dissociated cell culture systems that allow detailed observation of cell phenotypes but lack the highly ordered physiological neuron connection architecture. We describe here a platform comprising independent cell culture chambers separated by an array of "axonal diodes". This array involves asymmetric micro-channels, imposing unidirectional axon connectivity with 97% selectivity. It allows the construction of complex, oriented neuronal networks not feasible with earlier platforms. Different neuronal subtypes could be co-cultivated for weeks, and sequential seeding of different cell populations reproduced physiological network development. To illustrate possible applications, we created and characterized a cortico-striatal oriented network. Functional synaptic connections were established. The activation of striatal differentiation by cortical axons, and the synchronization of neural activity were demonstrated. Each neuronal population and subcompartment could be chemically addressed individually. The directionality of neural pathways being a key feature of the nervous system organization, the axon diode concept brings in a paradigmatic change in neuronal culture platforms, with potential applications for studying neuronal development, synaptic transmission and neurodegenerative disorder such as Alzheimer and Parkinson diseases at the sub-cellular, cellular and network levels.
Lab on a Chip 09/2011; 11(21):3663-73. · 5.67 Impact Factor
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ABSTRACT: Dendritic spines are postsynaptic structures the morphology of which correlates with the strength of synaptic efficacy. Measurements of spine density and spine morphology are achievable using recent imaging and bioinformatics tools. The three-dimensional automated analysis requires optimization of image acquisition and treatment. Here, we studied the critical steps for optimal confocal microscopy imaging of dendritic spines. We characterize the deconvolution process and show that it improves spine morphology analysis. With this method, images of dendritic spines from medium spiny neurons are automatically detected by the software Neuronstudio, which retrieves spine density as well as spine diameter and volume. This approach is illustrated with three-dimensional analysis of dendritic spines in a mouse model of Huntington's disease: the transgenic R6/2 mice. In symptomatic mutant mice, we confirm the decrease in spine density, and the method brings further information and show a decrease in spine volume and dendrite diameter. Moreover, we show a significant decrease in spine density at presymptomatic age which so far has gone unnoticed.
Brain Structure and Function 08/2011; 217(2):421-34. · 5.63 Impact Factor
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ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder due to abnormal polyglutamine expansion in huntingtin protein (Exp-Htt). This expansion causes protein aggregation, leading to neuronal dysfunction and death. We have previously shown that mitogen- and stress-activated kinase (MSK-1), a nuclear protein kinase involved in chromatin remodeling through histone H3 phosphorylation, is deficient in the striatum of HD patients and model mice. Restoring MSK-1 expression in cultured striatal cells prevented neuronal dysfunction and death induced by Exp-Htt. Here we extend these observations in a rat model of HD based on striatal lentiviral expression of Exp-Htt (LV-Exp-HTT). MSK-1 overexpression attenuated Exp-Htt-induced down-regulation of DARPP-32 expression 4 and 10 weeks after infection and enhanced NeuN staining after 10 weeks. LV-MSK-1 induced constitutive hyperphosphorylation of H3 and cAMP-responsive element binding protein (CREB), indicating that MSK-1 has spontaneous catalytic activity. MSK-1 overexpression also upregulated peroxisome proliferator-activated receptor γ coactivator alpha (PGC-1α), a transcriptional co-activator involved in mitochondrial biogenesis. Chromatin immunoprecipitation indicated that transcriptional regulation of PGC-1α is directly linked to increased binding of MSK-1, along with H3 and CREB phosphorylation of the PGC-1α promoter. MSK-1 knock-out mice showed spontaneous striatal atrophy as they aged, as well as higher susceptibility to systemic administration of the mitochondrial neurotoxin 3-NP. These results indicate that MSK-1 activation is an important and key event in the signaling cascade that regulates PGC-1α expression. Strategies aimed at restoring MSK-1 expression in the striatum might offer a new therapeutic approach to HD.
Human Molecular Genetics 06/2011; 20(12):2422-34. · 7.64 Impact Factor
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ABSTRACT: Cocaine-induced sensitization induces long-term neuroplastic changes in the striatum. Among these, extracellular signal-regulated kinase (ERK) is a fundamental component in striatal gene and epigenetic regulation and plays an important role in reward processes. As previous studies suggested that the chemokine CCL2 enhanced striatal dopamine release and as its cognate CCR2 receptor was located in brain structures implicated in cocaine reward, we tested the hypothesis that CCR2/CCL2 could be involved in cocaine-induced behavioral response. We used CCR2 knockout mice (CCR2(-/-)) and studied two crucial steps in cocaine sensitization: locomotor activity in sensitized mice and ERK activation in the striatum. We show that locomotor sensitization is significantly reduced in CCR2(-/-) mice as well as the dopamine transporter regulation and the cocaine-induced p-ERK striatal activation. Taken together, our results suggest that CCR2 receptor is involved in cocaine sensitization.
Journal of Molecular Neuroscience 03/2011; 44(3):147-51. · 2.50 Impact Factor
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ABSTRACT: Huntington’s disease (HD) is one of the most frequently found neurodegenerative disorders. Its main clinical manifestations
arc chorea, cognitive impairment and psychiatric disorders. It is an autosomal-dominant disorder with almost complete penetrance.
The mutation responsible for HD, unstable expansion of a CAG repcat, is located in the 5′ tcrminal section of the gene (ITJS) that encodes huntingtin protein (Htt). The pathophysiology of HD is not entirely clear. One intriguing characteristic of
HD is the special vulnerability of the striatum tomutated Htt, despite similar expression of the mutated protcin in other
brain regions. Aggregation of mutated Htt, transcriptional dysregulation, altered energy metabolism, excitotoxicity, impaired
axonal transport and altered synaptic transmission culminate in neuronal dysfianction and death. There is currently no way
ofpreventing or slowing down the disease progression and death usually occurs at about 20 years after dia
01/2011: pages 45-63;
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ABSTRACT: The ternary complex factor (TCF) Elk-1 is a transcription factor that regulates immediate early gene (IEG) expression via the serum response element (SRE) DNA consensus site. Elk-1 is associated with a dimer of serum response factor (SRF) at the SRE site, and its phosphorylation occurs at specific residues in response to mitogen-activated protein kinases (MAPKs), including c-Jun-N terminal kinase (JNK), p38/MAPK, and extracellular-signal regulated kinase (ERK). This phosphorylation event is critical for triggering SRE-dependent transcription. Although MAPKs are fundamental actors for the instatement and maintenance of memory, and much investigation of their downstream signaling partners have been conducted, no data yet clearly implicate Elk-1 in these processes. This is partly due to the complexity of Elk-1 sub-cellular localization, and hence functions, within neurons. Elk-1 is present in its resting state in the cytoplasm, where it colocalizes with mitochondrial proteins or microtubules. In this particular sub-cellular compartment, overexpression of Elk-1 is toxic for neuronal cells. When phosphorylated by the MAPK/ERK, Elk-1 translocates to the nucleus where it is implicated in regulating chromatin remodeling, SRE-dependent transcription, and neuronal differentiation. Another post-translational modification is the conjugation to SUMO (Small Ubiquitin-like MOdifier), which relocalizes Elk-1 in the cytoplasm. Thus, Elk-1 plays a dual role in neuronal functions: pro-apoptotic within the cytoplasm, and pro-differentiation within the nucleus. To address the role of Elk-1 in the brain, one must be aware of its multiple facets, and design molecular tools that will shut down Elk-1 expression, trafficking, or activation, in specific neuronal compartments. We summarize in this review the known molecular functions of Elk-1, its regulation in neuronal cells, and present evidence of its possible implication in model systems of synaptic plasticity, learning, but also in neurodegenerative diseases.
Frontiers in Neuroscience 01/2011; 5:35.
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ABSTRACT: Huntington's Disease (HD) is the most frequent neurodegenerative disease caused by an expansion of polyglutamines (CAG). The main clinical manifestations of HD are chorea, cognitive impairment, and psychiatric disorders. The transmission of HD is autosomal dominant with a complete penetrance. HD has a single genetic cause, a well-defined neuropathology, and informative pre-manifest genetic testing of the disease is available. Striatal atrophy begins as early as 15 years before disease onset and continues throughout the period of manifest illness. Therefore, patients could theoretically benefit from therapy at early stages of the disease. One important characteristic of HD is the striatal vulnerability to neurodegeneration, despite similar expression of the protein in other brain areas. Aggregation of the mutated Huntingtin (HTT), impaired axonal transport, excitotoxicity, transcriptional dysregulation as well as mitochondrial dysfunction, and energy deficits, are all part of the cellular events that underlie neuronal dysfunction and striatal death. Among these non-exclusive mechanisms, an alteration of striatal signaling is thought to orchestrate the downstream events involved in the cascade of striatal dysfunction.
Frontiers in Neuroanatomy 01/2011; 5:55. · 3.07 Impact Factor
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ABSTRACT: Activation of the extracellular signal-regulated kinase (ERK) in the striatum is crucial for long-term behavioral alterations induced by drugs of abuse. In response to cocaine, ERK phosphorylation (i.e., activation) is restricted to medium-sized spiny neurons expressing dopamine D1 receptor (D1R) and depends on a concomitant stimulation of D1R and glutamate N-methyl-D-aspartate receptor (NMDAR). However, the mechanisms responsible for this activation, especially the respective contribution of D1R and NMDAR, remain unknown.
We studied striatal neurons in culture stimulated with D1R agonist and/or glutamate and wild-type or genetically modified mice treated with cocaine. Biochemical, immunohistochemical, and imaging studies were performed. Mice were also subjected to behavioral experiments.
Stimulation of D1R cannot activate ERK by itself but potentiates glutamate-mediated calcium influx through NMDAR that is responsible for ERK activation. Potentiation of NMDAR by D1R depends on a cyclic adenosine monophosphate-independent signaling pathway, which involves tyrosine phosphorylation of the NR2B subunit of NMDAR by Src family kinases. We also demonstrate that the D1R/Src family kinases/NR2B pathway is responsible for ERK activation by cocaine in vivo. Inhibition of this pathway abrogates cocaine-induced locomotor sensitization and conditioned place preference.
Our results show that potentiation of NR2B-containing NMDAR by D1R is necessary and sufficient to trigger cocaine-induced ERK activation. They highlight a new cyclic adenosine monophosphate-independent pathway responsible for the integration of dopamine and glutamate signals by the ERK cascade in the striatum and for long-term behavioral alterations induced by cocaine.
Biological psychiatry 11/2010; 69(3):218-27. · 8.93 Impact Factor
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ABSTRACT: Huntington's disease (HD) is one of the most frequently found neurodegenerative disorders. Its main clinical manifestations are chorea, cognitive impairment and psychiatric disorders. It is an autosomal-dominant disorder with almost complete penetrance. The mutation responsible for HD, unstable expansion of a CAG repeat, is located in the 5' terminal section of the gene (IT15) that encodes huntingtin protein (Htt). The pathophysiology of HD is not entirely clear. One intriguing characteristic of HD is the special vulnerability of the striatum tomutated Htt, despite similar expression of the mutated protein in other brain regions. Aggregation of mutated Htt, transcriptional dysregulation, altered energy metabolism, excitotoxicity, impaired axonal transport and altered synaptic transmission culminate in neuronal dysfunction and death. There is currently no way of preventing or slowing down the disease progression and death usually occurs at about 20 years after diagnosis.
Advances in experimental medicine and biology 01/2010; 685:45-63. · 1.09 Impact Factor
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Stefania Fasano,
Angela D'Antoni,
Paul C Orban,
Emmanuel Valjent,
Elena Putignano,
Hugo Vara,
Tommaso Pizzorusso,
Maurizio Giustetto,
Bongjune Yoon,
Paul Soloway,
Rafael Maldonado, Jocelyne Caboche,
Riccardo Brambilla
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ABSTRACT: 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.
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.
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.
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.
Biological psychiatry 06/2009; 66(8):758-68. · 8.93 Impact Factor
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ABSTRACT: Nuclear translocation of activated extracellular signal-regulated kinases (ERK) in neurons is critical for gene regulations underlying long-term neuronal adaptation and memory formation. However, it is unknown how activated ERK travel from the post-synaptic elements where their activation occurs, to the nucleus where they translocate to exert their transcriptional roles. In cultured neurons, we identified endocytosis as a prime event in glutamate-induced nuclear trafficking of ERK2. We show that glutamate triggers a rapid recruitment of ERK2 to a protein complex comprising markers of the clathrin-dependent endocytotic and AMPA/glutamate receptor subtype. Inhibition of endocytosis results in a neuritic withholding of activated ERK2 without modification of ERK2 activity. As a consequence, endocytosis blockade alters ERK-dependent nuclear events, such as mitogen and stressed-activated kinase-1 (MSK-1) activation, histone H3 phosphorylation and gene regulations. Our data provide the first evidence that the endocytic pathway controls ERK nuclear translocation and ERK-dependent gene regulations induced by glutamate.
Molecular and Cellular Neuroscience 05/2009; 41(3):325-36. · 3.66 Impact Factor
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ABSTRACT: Drugs of abuse induce neuroadaptations through regulation of gene expression. Although much attention has focused on transcription factor activities, new concepts have recently emerged on the role of chromatin remodelling as a prerequisite for regulation of gene expression in neurons. Thus, for transcription to occur, chromatin must be decondensed, a dynamic process that depends on post-translational modifications of histones. We review here these modifications with a particular emphasis on the role of histone H3 phosphorylation at the promoter of specific genes, including c-fos and c-jun. We trace the signalling pathways involved in H3 phosphorylation and provide evidence for a role of mitogen and stress-activated protein kinase-1 (MSK1) downstream from the MAPK/extracellular-signal regulated kinase (ERK) cascade. In response to cocaine, MSK1 controls an early phase of histone H3 phosphorylation at the c-fos promoter in striatal neurons. MSK1 action may be potentiated by the concomitant inhibition of protein phosphatase 1 by nuclear translocation of dopamine- and cAMP-regulated phosphoprotein Mr = 32 000. H3 phosphorylation by MSK1 is critically involved in c-fos transcription, and cocaine-induced locomotor sensitization. Thus, ERK plays a dual role in gene regulation and drug addiction by direct activation of transcription factors and by chromatin remodelling.
Journal of Neurochemistry 02/2009; 108(6):1323-35. · 4.06 Impact Factor
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ABSTRACT: Huntington's disease (HD) is a polyglutamine-expanded related neurodegenerative disease. Despite the ubiquitous expression of expanded, polyQ-Huntingtin (ExpHtt) in the brain, striatal neurons present a higher susceptibility to the mutation. A commonly admitted hypothesis is that Dopaminergic inputs participate to this vulnerability. We previously showed that D2 receptor stimulation increased aggregate formation and neuronal death induced by ExpHtt in primary striatal neurons in culture, and chronic D2 antagonist treatment protects striatal dysfunctions induced by ExpHtt in a lentiviral-induced model system in vivo. The present work was designed to elucidate the signalling pathways involved, downstream D2 receptor (D2R) stimulation, in striatal vulnerability to ExpHtt.
Using primary striatal neurons in culture, transfected with a tagged-GFP version of human exon 1 ExpHtt, and siRNAs against D2R or D1R, we confirm that DA potentiates neuronal dysfunctions via D2R but not D1R stimulation. We demonstrate that D2 agonist treatment induces neuritic retraction and growth cone collapse in Htt- and ExpHtt expressing neurons. We then tested a possible involvement of the Rho/ROCK signalling pathway, which plays a key role in the dynamic of the cytoskeleton, in these processes. The pharmacological inhibitors of ROCK (Y27632 and Hydroxyfasudil), as well as siRNAs against ROCK-II, reversed D2-related effects on neuritic retraction and growth cone collapse. We show a coupling between D2 receptor stimulation and Rho activation, as well as hyperphosphorylation of Cofilin, a downstream effector of ROCK-II pathway. Importantly, D2 agonist-mediated potentiation of aggregate formation and neuronal death induced by ExpHtt, was totally reversed by Y27632 and Hydroxyfasudil and ROCK-II siRNAs.
Our data provide the first demonstration that D2R-induced vulnerability in HD is critically linked to the activation of the Rho/ROCK signalling pathway. The inclusion of Rho/ROCK inhibitors could be an interesting therapeutic option aimed at forestalling the onset of the disease.
PLoS ONE 01/2009; 4(12):e8287. · 4.09 Impact Factor
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ABSTRACT: Drugs used to treat Huntington's disease act on the symptoms but do not slow the disease process itself. This review focuses on recent pathogenetic findings and on emerging therapeutic approaches.
Basic research is providing novel insights into the complex molecular pathways involved in the pathogenesis of Huntington's disease. Several mechanisms have been identified that mediate neuronal dysfunction and death; these include neuronal aggregation of the mutated protein, transcriptional dysregulation, excitotoxicity, altered energy metabolism, impaired axonal transport, and altered synaptic transmission. Recent experimental works have identified potential new therapeutic targets. In particular, they emphasize the role of altered histone modifications in transcriptional dysregulation, the synergistic action of glutamatergic and dopaminergic pathways in inducing excitotoxicity, the neuroprotective effect of brain-derived neurotrophic factor expression and transport restoration, and the possibility of reducing the expression of the mutant protein huntingtin and its deleterious effects by using short interfering mRNAs.
Successful neuroprotective therapy for Huntington's disease patients is likely to involve a combined approach targeting both cellular and molecular mediators that account for the toxicity of mutated huntingtin.
Current Opinion in Neurology 09/2008; 21(4):497-503. · 4.94 Impact Factor
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ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder due to an abnormal polyglutamine expansion in the N-terminal region of huntingtin protein (Exp-Htt). This expansion causes protein aggregation and neuronal dysfunction and death. Transcriptional dysregulation due to Exp-Htt participates in neuronal death in HD. Here, using the R6/2 transgenic mouse model of HD, we identified a new molecular alteration that could account for gene dysregulation in these mice. Despite a nuclear activation of the mitogen-activated protein kinase/extracellular regulated kinase (ERK) along with Elk-1 and cAMP responsive element binding, two transcription factors involved in c-Fos transcription, we failed to detect any histone H3 phosphorylation, which is expected after nuclear ERK activation. Accordingly, we found in the striatum of these mice a deficiency of mitogen- and stress-activated kinase-1 (MSK-1), a kinase downstream ERK, critically involved in H3 phosphorylation and c-Fos induction. We extended this observation to Exp-Htt-expressing striatal neurons and postmortem brains of HD patients. In vitro, knocking out MSK-1 expression potentiated Exp-Htt-induced striatal death. Its overexpression induced H3 phosphorylation and c-Fos expression and totally protected against striatal neurodegeneration induced by Exp-Htt. We propose that MSK-1 deficiency is involved in transcriptional dysregulation and striatal degeneration. Restoration of its expression and activity may be a new therapeutic target in HD.
The FASEB Journal 05/2008; 22(4):1083-93. · 5.71 Impact Factor
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Camille Brochier,
Marie-Claude Gaillard,
Elsa Diguet,
Nicolas Caudy,
Carole Dossat,
Béatrice Ségurens,
Patrick Wincker,
Emmanuel Roze, Jocelyne Caboche,
Philippe Hantraye,
Emmanuel Brouillet,
Jean-Marc Elalouf,
Michel de Chaldée
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ABSTRACT: Using serial analysis of gene expression, we collected quantitative transcriptome data in 11 regions of the adult wild-type mouse brain: the orbital, prelimbic, cingulate, motor, somatosensory, and entorhinal cortices, the caudate-putamen, the nucleus accumbens, the thalamus, the substantia nigra, and the ventral tegmental area. With >1.2 million cDNA tags sequenced, this database is a powerful resource to explore brain functions and disorders. As an illustration, we performed interregional comparisons and found 315 differential transcripts. Most of them are poorly characterized and 20% lack functional annotation. For 78 differential transcripts, we provide independent expression level measurements in mouse brain regions by real-time quantitative RT-PCR. We also show examples where we used in situ hybridization to achieve infrastructural resolution. For 30 transcripts, we next demonstrated that regional enrichment is conserved in the human brain. We then quantified the expression levels of region-enriched transcripts in the R6/2 mouse model of Huntington disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson disease and observed significant alterations in the striatum, cerebral cortex, thalamus and substantia nigra of R6/2 mice and in the striatum of MPTP-treated mice. These results show that the gene expression data provided here for the mouse brain can be used to explore pathophysiological models and disclose transcripts differentially expressed in human brain regions.
Physiological Genomics 04/2008; 33(2):170-9. · 2.73 Impact Factor
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Delphine Charvin,
Emmanuel Roze,
Valérie Perrin,
Carole Deyts,
Sandrine Betuing,
Christiane Pagès,
Etienne Régulier,
Ruth Luthi-Carter,
Emmanuel Brouillet,
Nicole Déglon, Jocelyne Caboche
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ABSTRACT: Huntington's disease (HD) results from an abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation causes preferential degeneration of striatal projection neurons. We previously demonstrated, in vitro, that dopaminergic D2 receptor stimulation acted synergistically with mutated huntingtin (expHtt) to increase aggregate formation and striatal death. In the present work, we extend these observations to an in vivo system based on lentiviral-mediated expression of expHtt in the rat striatum. The early and chronic treatment with the D2 antagonist haloperidol decanoate protects striatal neurons from expHtt-induced dysfunction, as analyzed by DARPP-32 and NeuN stainings. Haloperidol treatment also reduces aggregates formation, an effect that is maintained over time. These findings indicate that D2 receptors activation contributes to the deleterious effects of expHtt on striatal function and may represent an interesting early target to alter the subsequent course of neuropathology in HD.
Neurobiology of Disease 02/2008; 29(1):22-9. · 5.40 Impact Factor
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ABSTRACT: The transcription factor Elk-1 plays a key role in cell differentiation, proliferation and apoptosis. This role is thought to arise from its phosphorylation by activated extracellular signal-regulated kinases (ERKs), a critical posttranslational event for the transcriptional activity of the ternary complex composed of Elk-1 and a dimer of serum response factor (SRF) at the serum response element (SRE) regulatory site of transcription. In addition to its nuclear localization, Elk-1 is found in the dendrites and soma of neuronal cells and recent evidence implicate a cytoplasmic proapoptotic function of Elk-1, via its association with the mitochondrial permeability transition pore complex. Thus, the nuclear versus cytoplasmic localization of Elk-1 seems to be crucial for its biological function. In this study we show that the excitatory neurotransmitter, glutamate, induces an ERK-dependent Elk-1 activation and nuclear relocalization. We demonstrate that Elk-1 phosphorylation on Ser383/389 has a dual function and triggers both Elk-1 nuclear translocation and SRE-dependent gene expression. Mutating these sites into inactive residues or using a synthetic penetrating peptide (TAT-DEF-Elk-1), which specifically interferes with the DEF docking domain of Elk-1, prevents Elk-1 nuclear translocation without interfering with ERK nor MSK1 (mitogen- and stress-activated protein kinase 1), a CREB kinase downstream from ERK- activation. This results in a differential regulation of glutamate-induced IEG regulation when compared with classical inhibitors of the ERK pathway. Using the TAT-DEF-Elk-1 peptide or the dominant-negative version of Elk-1, we show that Elk-1 phosphorylation controls dendritic elongation, SRF and Actin expression levels as well as cytoskeleton dynamics.
Journal of Neuroscience 01/2008; 27(52):14448-58. · 7.11 Impact Factor
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ABSTRACT: Chromatin remodelling is thought to play a key role in gene regulation that underlies long-term synaptic plasticity and memory formation. The dynamic process of chromatin remodelling requires post-translational modifications of histones, a group of highly basic proteins that are tightly linked to DNA. In the present study, we investigated histone H3 modifications in response to glutamate stimulation leading to c-Fos and c-Jun induction in an in vitro model system of striatal neurons in culture. Intracellular signalling pathways implicated in these modifications were analysed. Histone H3 acetylation was strong in basal conditions and unmodified by glutamate treatment. By contrast, glutamate induced a strong phosphorylation of histone H3 that was inhibited by selective inhibitors of the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38 MAPK) pathways, U0126 and SB203580, respectively. Blocking activation of mitogen- and stress-activated kinase 1 (MSK1), a kinase downstream ERK and p38 MAPK, by pharmacological approach or using striatal cells from MSK1 deficient mice, totally abolished H3 phosphorylation, as well as c-Fos and c-Jun induction. Chromatin immunoprecipitation assays confirmed increased levels of phosphorylated H3 at the c-jun promoter. Altogether, our data highlight the crucial role of MSK1 in the nucleosomal response necessary for gene induction in neuronal cells.
Journal of Neurochemistry 06/2007; 101(3):697-708. · 4.06 Impact Factor
