23 results on '"Laurie Galvan"'
Search Results
2. Major motor and gait deficits with sexual dimorphism in a Shank3 mutant mouse model
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Emmanuel Matas, Alexandre Maisterrena, Mathieu Thabault, Eric Balado, Maureen Francheteau, Anais Balbous, Laurie Galvan, and Mohamed Jaber
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Gait ,Sociability ,Motor coordination ,Cerebellum ,Crus I ,Crus II ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Contrasting findings were reported in several animal models with a Shank3 mutation used to induce various autism spectrum disorder (ASD) symptoms. Here, we aimed at investigating behavioral, cellular, and molecular consequences of a C-terminal (frameshift in exon 21) deletion in Shank3 protein in mice, a mutation that is also found in clinical conditions and which results in loss of major isoforms of Shank3. A special focus was made on cerebellar related parameters. Methods All three genotypes were analyzed [wild type (WT), heterozygote (Shank3+/ΔC) and homozygote (Shank3 ΔC/ΔC)] and males and females were separated into two distinct groups. Motor and social behavior, gait, Purkinje cells (PC) and glutamatergic protein levels were determined. Behavioral and cellular procedures used here were previously validated using two environmental animal models of ASD. ANOVA and post-hoc analysis were used for statistical analysis. Results Shank3 ΔC/ΔC mice showed significant impairments in social novelty preference, stereotyped behavior and gait. These were accompanied by a decreased number of PC in restricted cerebellar sub-regions and decreased cerebellar expression of mGluR5. Females Shank3 ΔC/ΔC were less affected by the mutation than males. Shank3+/ΔC mice showed impairments only in social novelty preference, grooming, and decreased mGluR5 expression and that were to a much lesser extent than in Shank3 ΔC/ΔC mice. Limitations As Shank3 mutation is a haploinsufficiency, it is of interest to emphasize that Shank3+/ΔC mice showed only mild to no deficiencies compared to Shank3 ΔC/ΔC. Conclusions Our findings indicate that several behavioral, cellular, and molecular parameters are affected in this animal model. The reported deficits are more pronounced in males than in females. Additionally, male Shank3 ΔC/ΔC mice show more pronounced alterations than Shank3+/ΔC. Together with our previous findings in two environmental animal models of ASD, our studies indicate that gait dysfunction constitutes a robust set of motor ASD symptoms that may be considered for implementation in clinical settings as an early and quantitative diagnosis criteria. more...
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- 2021
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Catalog
3. Major Contribution of Somatostatin-Expressing Interneurons and Cannabinoid Receptors to Increased GABA Synaptic Activity in the Striatum of Huntington’s Disease Mice
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Sandra M. Holley, Laurie Galvan, Talia Kamdjou, Ashley Dong, Michael S. Levine, and Carlos Cepeda
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striatum ,Huntington’s disease (HD) ,GABA interneurons ,CB1 receptors ,electrophysiology ,optogenetics ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Huntington’s disease (HD) is a heritable neurological disorder that affects cognitive and motor performance in patients carrying the mutated huntingtin (HTT) gene. In mouse models of HD, previous reports showed a significant increase in spontaneous GABAA receptor-mediated synaptic activity in striatal spiny projection neurons (SPNs). In this study, using optogenetics and slice electrophysiology, we examined the contribution of γ-aminobutyric acid (GABA)-ergic parvalbumin (PV)- and somatostatin (SOM)-expressing interneurons to the increase in GABA neurotransmission using the Q175 (heterozygote) mouse model of HD. Patch clamp recordings in voltage-clamp mode were performed on SPNs from brain slices of presymptomatic (2 months) and symptomatic (8 and 12 months) Q175 mice and wildtype (WT) littermates. While inhibitory postsynaptic currents (IPSCs) evoked in SPNs following optical activation of PV- and SOM-expressing interneurons differed in amplitude, no genotype-dependent differences were observed at all ages from both interneuron types; however, responses evoked by either type were found to have faster kinetics in symptomatic mice. Since SOM-expressing interneurons are constitutively active in striatal brain slices, we then examined the effects of acutely silencing these neurons in symptomatic mice with enhanced Natronomonas pharaonis halorhodopsin (eNpHR). Optically silencing SOM-expressing interneurons resulted in a greater decrease in the frequency of spontaneous IPSCs (sIPSCs) in a subset of SPNs from Q175 mice compared to WTs, suggesting that SOM-expressing interneurons are the main contributors to the overall increased GABA synaptic activity in HD SPNs. Additionally, the effects of activating GABAB and cannabinoid (CB1) receptors were investigated to determine whether these receptors were involved in modulating interneuron-specific GABA synaptic transmission and if this modulation differed in HD mice. When selectively activating PV- and SOM-expressing interneurons in the presence of the CB1 receptor agonist WIN-55,212, the magnitudes of the evoked IPSCs in SPNs decreased for both interneuron types although this change was less prominent in symptomatic Q175 SPNs during SOM-expressing interneuron activation. Overall, these findings show that dysfunction of SOM-expressing interneurons contributes to the increased GABA synaptic activity found in HD mouse models and that dysregulation of the endocannabinoid system may contribute to this effect. more...
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- 2019
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4. Age‐related behavioural and striatal dysfunctions in Shank3 ΔC/ΔC mouse model of autism spectrum disorder
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Mathieu Thabault, Valentine Turpin, Éric Balado, Cloé Fernandes‐Gomes, Anne‐Lise Huot, Anne Cantereau, Pierre‐Olivier Fernagut, Mohamed Jaber, and Laurie Galvan
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General Neuroscience - Published
- 2023
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5. Author response for 'Age‐related behavioral and striatal dysfunctions in Shank3 ΔC/ΔC mouse model of autism spectrum disorder'
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null Mathieu Thabault, null Valentine Turpin, null Éric Balado, null Cloé Fernandes‐Gomes, null Anne‐Lise Huot, null Anne Cantereau, null Pierre‐Olivier Fernagut, null Mohamed Jaber, and null Laurie Galvan more...
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- 2022
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6. Cerebellar and Striatal Implications in Autism Spectrum Disorders: From Clinical Observations to Animal Models
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Mathieu Thabault, Valentine Turpin, Alexandre Maisterrena, Mohamed Jaber, Matthieu Egloff, and Laurie Galvan
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Neurons ,Autism Spectrum Disorder ,Organic Chemistry ,General Medicine ,Corpus Striatum ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,Purkinje Cells ,Cerebellum ,Models, Animal ,Animals ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy - Abstract
Autism spectrum disorders (ASD) are complex conditions that stem from a combination of genetic, epigenetic and environmental influences during early pre- and postnatal childhood. The review focuses on the cerebellum and the striatum, two structures involved in motor, sensory, cognitive and social functions altered in ASD. We summarize clinical and fundamental studies highlighting the importance of these two structures in ASD. We further discuss the relation between cellular and molecular alterations with the observed behavior at the social, cognitive, motor and gait levels. Functional correlates regarding neuronal activity are also detailed wherever possible, and sexual dimorphism is explored pointing to the need to apprehend ASD in both sexes, as findings can be dramatically different at both quantitative and qualitative levels. The review focuses also on a set of three recent papers from our laboratory where we explored motor and gait function in various genetic and environmental ASD animal models. We report that motor and gait behaviors can constitute an early and quantitative window to the disease, as they often correlate with the severity of social impairments and loss of cerebellar Purkinje cells. The review ends with suggestions as to the main obstacles that need to be surpassed before an appropriate management of the disease can be proposed. more...
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- 2022
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7. Striatal <scp>GABA</scp> ergic interneuron dysfunction in the Q175 mouse model of Huntington's disease
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Michael S. Levine, Laurie Galvan, Talia Kamdjou, Sandra M. Holley, and Carlos Cepeda
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Male ,Interneuron ,Action Potentials ,Mice, Transgenic ,Striatum ,Synaptic Transmission ,Article ,Sholl analysis ,03 medical and health sciences ,0302 clinical medicine ,Huntington's disease ,Interneurons ,medicine ,Animals ,GABAergic Neurons ,030304 developmental biology ,0303 health sciences ,biology ,musculoskeletal, neural, and ocular physiology ,General Neuroscience ,Excitatory Postsynaptic Potentials ,Dendrites ,medicine.disease ,Corpus Striatum ,Disease Models, Animal ,Electrophysiology ,Huntington Disease ,medicine.anatomical_structure ,Inhibitory Postsynaptic Potentials ,nervous system ,biology.protein ,Excitatory postsynaptic potential ,GABAergic ,Female ,Neuroscience ,030217 neurology & neurosurgery ,Parvalbumin - Abstract
The pathological hallmark of Huntington’s disease (HD) is the massive loss of striatal and cortical neurons. Until recently, it was believed that striatal interneurons were spared from degeneration. This view has changed after the demonstration that parvalbumin (PV)-expressing interneurons also are vulnerable in humans. Here we compared morphological and functional changes of striatal fast-spiking interneurons (FSIs) and low-threshold spiking (LTS) interneurons in the Q175 mouse model of HD at presymptomatic (2 months) and symptomatic (12 months) stages of the disease. Electrophysiological intrinsic and synaptic properties of FSIs were significantly altered in symptomatic mice compared to wild-type (WT) littermates. Overall, FSIs became more excitable with disease progression. Sholl analysis also revealed a significant loss of dendritic complexity and excitatory synaptic inputs. The basic membrane and synaptic properties of LTS interneurons were similar in Q175 and WT mice regardless of disease stage. The resilience of LTS interneurons could be related to their sparsity of excitatory synaptic inputs compared with FSIs. However, in symptomatic mice, a subpopulation of LTS interneurons displayed an increase in action potential firing within oscillating bursts. Thus, we conclude that while both FSI and LTS interneurons demonstrate increases in excitability, the HD mutation differentially affects their membrane and synaptic properties as well as their ability to respond to compensatory challenges presented during the late stage of the disease. Alterations in GABAergic interneuron intrinsic activity and responsiveness to incoming signals may significantly affect SPN output thus contributing to abnormal motor movements in patients afflicted with HD. more...
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- 2018
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8. Major Contribution of Somatostatin-Expressing Interneurons and Cannabinoid Receptors to Increased GABA Synaptic Activity in the Striatum of Huntington's Disease Mice
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Carlos Cepeda, Michael S. Levine, Talia Kamdjou, Laurie Galvan, Sandra M. Holley, and Ashley Dong
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0301 basic medicine ,Huntingtin ,Cannabinoid receptor ,Interneuron ,striatum ,Neurotransmission ,Biology ,Medium spiny neuron ,Inhibitory postsynaptic potential ,Huntington’s disease (HD) ,lcsh:RC321-571 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,medicine ,optogenetics ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Original Research ,GABAA receptor ,musculoskeletal, neural, and ocular physiology ,Cell Biology ,electrophysiology ,GABA interneurons ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,biology.protein ,Neuroscience ,CB1 receptors ,030217 neurology & neurosurgery ,Parvalbumin - Abstract
Huntington’s disease (HD) is a heritable neurological disorder that affects cognitive and motor performance in patients carrying the mutated huntingtin (HTT) gene. In mouse models of HD, previous reports showed a significant increase in spontaneous GABAA receptor-mediated synaptic activity in striatal spiny projection neurons (SPNs). In this study, using optogenetics and slice electrophysiology, we examined the contribution of γ-aminobutyric acid (GABA)-ergic parvalbumin (PV)- and somatostatin (SOM)-expressing interneurons to the increase in GABA neurotransmission using the Q175 (heterozygote) mouse model of HD. Patch clamp recordings in voltage-clamp mode were performed on SPNs from brain slices of presymptomatic (2 months) and symptomatic (8 and 12 months) Q175 mice and wildtype (WT) littermates. While inhibitory postsynaptic currents (IPSCs) evoked in SPNs following optical activation of PV- and SOM-expressing interneurons differed in amplitude, no genotype-dependent differences were observed at all ages from both interneuron types; however, responses evoked by either type were found to have faster kinetics in symptomatic mice. Since SOM-expressing interneurons are constitutively active in striatal brain slices, we then examined the effects of acutely silencing these neurons in symptomatic mice with enhanced Natronomonas pharaonis halorhodopsin (eNpHR). Optically silencing SOM-expressing interneurons resulted in a greater decrease in the frequency of spontaneous IPSCs (sIPSCs) in a subset of SPNs from Q175 mice compared to WTs, suggesting that SOM-expressing interneurons are the main contributors to the overall increased GABA synaptic activity in HD SPNs. Additionally, the effects of activating GABAB and cannabinoid (CB1) receptors were investigated to determine whether these receptors were involved in modulating interneuron-specific GABA synaptic transmission and if this modulation differed in HD mice. When selectively activating PV- and SOM-expressing interneurons in the presence of the CB1 receptor agonist WIN-55,212, the magnitudes of the evoked IPSCs in SPNs decreased for both interneuron types although this change was less prominent in symptomatic Q175 SPNs during SOM-expressing interneuron activation. Overall, these findings show that dysfunction of SOM-expressing interneurons contributes to the increased GABA synaptic activity found in HD mouse models and that dysregulation of the endocannabinoid system may contribute to this effect. more...
- Published
- 2019
9. CREB controls cortical circuit plasticity and functional recovery after stroke
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Laurie Galvan, Sandra M. Holley, Alcino J. Silva, L. Caracciolo, Máté Marosi, Riki Kawaguchi, Shahrzad Latifi, Yoshitake Sano, Carlos Portera-Cailliau, Javier Mazzitelli, Giovanni Coppola, S. T. Carmichael, Michael S. Levine, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Instituto de Plasmas e Fusão Nuclear [Lisboa] (IPFN), Instituto Superior Técnico, Universidade Técnica de Lisboa (IST), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA) more...
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0301 basic medicine ,Male ,Patch-Clamp Techniques ,medicine.medical_treatment ,General Physics and Astronomy ,Somatosensory system ,Inbred C57BL ,Mice ,0302 clinical medicine ,2.1 Biological and endogenous factors ,Medicine ,Aetiology ,lcsh:Science ,Cyclic AMP Response Element-Binding Protein ,Stroke ,ComputingMilieux_MISCELLANEOUS ,Motor Neurons ,Brain Mapping ,Multidisciplinary ,Neuronal Plasticity ,biology ,Rehabilitation ,Motor Cortex ,medicine.anatomical_structure ,Neurological ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Stroke recovery ,Motor cortex ,Science ,CREB ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Neuroplasticity ,Genetics ,Gene silencing ,Animals ,cardiovascular diseases ,Transcription factor ,business.industry ,Gene Expression Profiling ,Neurosciences ,General Chemistry ,Recovery of Function ,medicine.disease ,Brain Disorders ,Mice, Inbred C57BL ,030104 developmental biology ,biology.protein ,lcsh:Q ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Treatments that stimulate neuronal excitability enhance motor performance after stroke. cAMP-response-element binding protein (CREB) is a transcription factor that plays a key role in neuronal excitability. Increasing the levels of CREB with a viral vector in a small pool of motor neurons enhances motor recovery after stroke, while blocking CREB signaling prevents stroke recovery. Silencing CREB-transfected neurons in the peri-infarct region with the hM4Di-DREADD blocks motor recovery. Reversing this inhibition allows recovery to continue, demonstrating that by manipulating the activity of CREB-transfected neurons it is possible to turn off and on stroke recovery. CREB transfection enhances remapping of injured somatosensory and motor circuits, and induces the formation of new connections within these circuits. CREB is a central molecular node in the circuit responses after stroke that lead to recovery from motor deficits., Increasing excitability in the peri-infarct area enhances motor recovery after stroke. Here the authors show that expressing CREB, a transcription factor known for its role in synaptic plasticity, or increasing activity of CREB-expressing cells near the stroke site improves recovery in an effect that is strong enough that it can be used to turn on and off motor recovery after stroke. more...
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- 2018
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10. CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington’s disease
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Sandrine Betuing, Anabelle Planques, Françoise Piguet, Gaëtan Despres, Jocelyne Caboche, Christiane Pagès, Nicolas Heck, Lara Moumné, Nathalie Cartier, Amelie Hu, Laurie Galvan, Antonin Lamaziere, Susanne Bolte, Lydie Boussicault, Sandro Alves, Patrick Aubourg, Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Pierre et Marie Curie - Paris 6 (UPMC), Développement et Neuropharmacologie / Development and Neuropharmacology, Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF (institution))-Université Paris sciences et lettres (2020-....) (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Collège de France (CdF (institution))-Université Paris sciences et lettres (2020-....) (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences du végétal (ISV), Centre National de la Recherche Scientifique (CNRS), Laboratory of Experimental Neurology, Université libre de Bruxelles (ULB), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Center for Neurobehavioral Genetics, Semel Institute, University of California, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Neurogénétique moléculaire, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Development and Neuropharmacology, Center for Interdisciplinary Research in Biology (INSERM CNRS 7141), Collège de France (CdF), Université Libre de Bruxelles [Bruxelles] (ULB), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of California (UC), d'Eggis, Gilles, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut de Biologie Paris-Seine more...
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0301 basic medicine ,Male ,Huntingtin ,striatum ,Striatum ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Desmosterol ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,Aged, 80 and over ,Cerebral Cortex ,Putamen ,Huntington's disease ,Middle Aged ,Neuroprotection ,3. Good health ,CYP46A1 ,Cholesterol ,medicine.anatomical_structure ,Huntington Disease ,Cerebral cortex ,lipids (amino acids, peptides, and proteins) ,Female ,neuroprotection ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Huntington’s disease ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Biology ,03 medical and health sciences ,Neurologie ,Internal medicine ,mental disorders ,medicine ,Cholesterol 24-Hydroxylase ,Animals ,Humans ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Cholesterol 24-hydroxylase ,Aged ,cholesterol ,Original Articles ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,chemistry ,nervous system ,Steroid Hydroxylases ,Mice, Inbred CBA ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
Huntington's disease is an autosomal dominant neurodegenerative disease caused by abnormal polyglutamine expansion in huntingtin (Exp-HTT) leading to degeneration of striatal neurons. Altered brain cholesterol homeostasis has been implicated in Huntington's disease, with increased accumulation of cholesterol in striatal neurons yet reduced levels of cholesterol metabolic precursors. To elucidate these two seemingly opposing dysregulations, we investigated the expression of cholesterol 24-hydroxylase (CYP46A1), the neuronal-specific and rate-limiting enzyme for cholesterol conversion to 24S-hydroxycholesterol (24S-OHC). CYP46A1 protein levels were decreased in the putamen, but not cerebral cortex samples, of post-mortem Huntington's disease patients when compared to controls. Cyp46A1 mRNA and CYP46A1 protein levels were also decreased in the striatum of the R6/2 Huntington's disease mouse model and in SThdhQ111 cell lines. In vivo, in a wild-type context, knocking down CYP46A1 expression in the striatum, via an adeno-associated virus-mediated delivery of selective shCYP46A1, reproduced the Huntington's disease phenotype, with spontaneous striatal neuron degeneration and motor deficits, as assessed by rotarod. In vitro, CYP46A1 restoration protected SThdhQ111 and Exp-HTT-expressing striatal neurons in culture from cell death. In the R6/2 Huntington's disease mouse model, adeno-associated virus-mediated delivery of CYP46A1 into the striatum decreased neuronal atrophy, decreased the number, intensity level and size of Exp-HTT aggregates and improved motor deficits, as assessed by rotarod and clasping behavioural tests. Adeno-associated virus-CYP46A1 infection in R6/2 mice also restored levels of cholesterol and lanosterol and increased levels of desmosterol. In vitro, lanosterol and desmosterol were found to protect striatal neurons expressing Exp-HTT from death. We conclude that restoring CYP46A1 activity in the striatum promises a new therapeutic approach in Huntington's disease., SCOPUS: ar.j, info:eu-repo/semantics/published more...
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- 2016
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11. Mitochondria in Huntington's disease
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Nicole Déglon, Laurie Galvan, Maria Damiano, Emmanuel Brouillet, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Center for Neurobehavioral Genetics, Semel Institute, University of California, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institut d'Imagerie BioMédicale (I2BM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, and University of California (UC) more...
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Dopamine ,Excitotoxicity ,Nerve Tissue Proteins ,Striatum ,Biology ,Mitochondrion ,medicine.disease_cause ,NMDA receptors ,Oxidative Phosphorylation ,Mitochondrial Proteins ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Neurochemical ,Huntington's disease ,medicine ,Huntingtin Protein ,Animals ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,Glutamate receptor ,medicine.disease ,NMDA receptor ,Corpus Striatum ,mitochondria ,Huntington Disease ,Biochemistry ,nervous system ,Molecular Medicine ,Calcium ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Glutamate ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
International audience; Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The disease is caused by an abnormal expansion of a CAG repeat located in exon 1 of the gene encoding the huntingtin protein (Htt) that confers a toxic function to the protein. The most striking neuropathological change in HD is the preferential loss of medium spiny GABAergic neurons in the striatum. The mechanisms underlying striatal vulnerability in HD are unknown, but compelling evidence suggests that mitochondrial defects may play a central role. Here we review recent findings supporting this hypothesis. Studies investigating the toxic effects of mutant Htt in cell culture or animal models reveal mitochondrial changes including reduction of Ca buffering capacity, loss of membrane potential, and decreased expression of oxidative phosphorylation (OXPHOS) enzymes. Striatal neurons may be particularly vulnerable to these defects. One hypothesis is that neurotransmission systems such as dopamine and glutamate exacerbate mitochondrial defects in the striatum. In particular, mitochondrial dysfunction facilitates impaired Ca homeostasis linked to the glutamate receptor-mediated excitotoxicity. Also dopamine receptors modulate mutant Htt toxicity, at least in part through regulation of the expression of mitochondrial complex II. All these observations support the hypothesis that mitochondria, acting as "sensors" of the neurochemical environment, play a central role in striatal degeneration in HD. more...
- Published
- 2010
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12. Behavioral phenotyping of heterozygous acetylcholinesterase knockout (AChE+/−) mice showed no memory enhancement but hyposensitivity to amnesic drugs
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Vanessa Rana-Poussine, Julie Espallergues, Arnaud Chatonnet, Laurie Galvan, Tangui Maurice, Florence Sabatier, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Center for Neurobehavioral Genetics, Semel Institute, University of California, Vascular research center of Marseille (VRCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-École pratique des hautes études (EPHE), Département de Physiologie Animale (INRA), Institut National de la Recherche Agronomique (INRA), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Dynamique Musculaire et Métabolisme (DMEM), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of California (UC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 2 - Sciences et Techniques (UM2)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation Cellulaire et Croissance (DCC), and Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2) more...
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Male ,Hippocampus ,Mice ,Behavioral Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Muscarinic acetylcholine receptor ,troubles de l'apprentissage ,ComputingMilieux_MISCELLANEOUS ,Cerebral Cortex ,Mice, Knockout ,0303 health sciences ,récepteurs muscariniques ,acetylcholinesterase ,Acetylcholinesterase ,Memory, Short-Term ,Phenotype ,Nicotinic agonist ,Knockout mouse ,language ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,learning and memory ,Heterozygote ,medicine.medical_specialty ,Aché ,Muscarinic Antagonists ,Motor Activity ,récepteurs nicotiniques ,scopolamine ,03 medical and health sciences ,Sex Factors ,hippocampe ,Internal medicine ,medicine ,Animals ,Maze Learning ,030304 developmental biology ,Analysis of Variance ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Antagonist ,Peptide Fragments ,language.human_language ,Endocrinology ,chemistry ,Exploratory Behavior ,Cholinergic ,amyloid toxicity ,Lipid Peroxidation ,Neuroscience ,030217 neurology & neurosurgery ,knockout model - Abstract
E-mail Address: maurice@univ-montp2.fr, chatonnet@ensam.inra.fr; International audience; Decrease in the expression or activity of acetylcholinesterase (ACH) enzymatic activity results in increased cholinergic tonus in the brain and periphery, with concomitant regulations of nicotinic and muscarinic receptors expression. We generated AChE knockout mice and characterized the behavioral phenotype of heterozygous animals, focusing on learning and memory functions. Male and female, AChE(+/-) and AChE(+/+) littermate controls (129sv strain) were tested at 5-9 weeks of age. AChE activity was significantly decreased in the hippocampus and cortex of AChE(+/-) mice, but butyrylcholinesterase activity was preserved. AChE(+/-) mice failed to show any difference in terms of locomotion, exploration and anxiety parameters in the open-field test. Animals were then tested for place learning in the water-maze. They were trained using a 'sustained acquisition' protocol (3 swim trials per day) or a 'mild acquisition' protocol (2 swim trials per day) to locate an invisible platform in fixed position (reference memory procedure). Then, during 3 days, they were trained to locate the platform in a variable position (working memory procedure). Learning profiles and probe test performances were similar for AChE(+/-) and AChE(+/+) mice. Mice were then treated with the muscarinic receptor antagonist scopolamine (0.5, 5 mg/kg) 20 min before each training session. Scopolamine impaired learning at both doses in AChE(+/+) mice, but only at the highest dose in AChE(+/-) mice. Moreover, the intracerebroventricular injection of amyloid-beta(25-35) peptide, 9 nmol, 7 days before water-maze acquisition, failed to induce learning deficits in AChE(+/-) mice, but impaired learning in AChE(+/+) controls. The peptide failed to be toxic in forebrain structures of AChE(+/-) mice, since an increase in lipid peroxidation levels was measured in the hippocampus of AChE(+/+) but not AChE(+/-) mice. We conclude that the increase in cholinergic tonus observed in AChE(+/-) mice did not result in increased memory functions but allowed a significant prevention of the deleterious effects of muscarinic blockade or amyloid toxicity. more...
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- 2010
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13. Rhes, a protein with selective expression in the striatum, plays a major role in Huntington’s disease pathogenesis
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Laurie Galvan and Emmanuel Brouillet
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congenital, hereditary, and neonatal diseases and abnormalities ,Choreiform movement ,Striatum ,Polyglutamine tract ,Biology ,medicine.disease ,nervous system diseases ,Pathogenesis ,Exon ,nervous system ,Neurology ,Huntington's disease ,mental disorders ,Huntingtin Protein ,medicine ,Small GTPase ,Neurology (clinical) ,Neuroscience - Abstract
Evaluation of: Subramaniam S, Sixt KM, Barrow R, Snyder SH: Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 324, 1327–1330 (2009). Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by choreiform movements, cognitive deficits and psychiatric disturbances. The disease is caused by an abnormal expansion of a CAG repeat located in exon 1 of the gene encoding the huntingtin protein (Htt). The genetic defect encodes a polyglutamine tract in the N-terminal part of Htt that confers a toxic function to the protein. The most striking neuropathological hallmark in HD patients is the selective atrophy of the striatum. The mechanisms underlying the particular vulnerability of the striatum are unknown. Subramaniam and collaborators demonstrate that the cytotoxicity of mutant Htt is greatly enhanced in the presence of the small GTPase, Rhes, a protein of unclear function that has a preferential expression in the striatum. The study demonstrates that Rhes is an E3 ligase, interacts with mutant Htt and modifies it through SUMOylation, a post-transcriptional process that consists of the addition of the protein SUMO1 to mutant Htt. By contrast, the GTPase activity of Rhes does not seem to be involved in the toxicity of mutant Htt. The Rhes-mediated sumoylation of mutant Htt eventually leads to reduced levels of neuroprotective insoluble aggregates, and increased levels of the toxic soluble form of mutant Htt. These completely novel results shed new light on HD pathogenesis. The selective expression of Rhes in the striatum and its role in mutant Htt toxicity could explain why the striatum is so vulnerable in HD. This work may lead to new therapeutic strategies targeting Rhes. more...
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- 2009
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14. Striatal long noncoding RNA Abhd11os is neuroprotective against an N-terminal fragment of mutant huntingtin in vivo
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Laurie Galvan, Martine Guillermier, Gilles Bonvento, Laetitia Francelle, Nicole Déglon, Michel de Chaldée, Marie-Claude Gaillard, Emmanuel Brouillet, Benoit Bernay, Fanny Petit, Jean-Marc Elalouf, Noelle Dufour, Philippe Hantraye, Service MIRCEN ( MIRCEN ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Institut de Biologie et de Technologies de Saclay ( IBITECS ), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Epigénomique des mammifères ( REMOD ), Département Biologie des Génomes ( DBG ), Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Center for Neurobehavioral Genetics, Semel Institute, University of California, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Interactions Cellules Organismes Environnement (ICORE), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Service de Biologie Intégrative et Génétique Moléculaire (SBIGeM), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut d'Imagerie BioMédicale (I2BM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), University of California (UC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut de Biologie et de Technologies de Saclay (IBITECS), Epigénomique des mammifères (REMOD), Département Biologie des Génomes (DBG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA) more...
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Male ,Aging ,Huntingtin ,RNA, Untranslated ,[SDV]Life Sciences [q-bio] ,Mutant ,Gene Expression ,Noncoding RNA ,Small hairpin RNA ,RNA, Small Interfering ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,Regulation of gene expression ,Gene knockdown ,Huntingtin Protein ,Reverse Transcriptase Polymerase Chain Reaction ,General Neuroscience ,Neurodegeneration ,Nuclear Proteins ,Huntington disease ,Non-coding RNA ,Neuroprotection ,Neuroprotective Agents ,Female ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neuroscience(all) ,Clinical Neurology ,Down-Regulation ,Nerve Tissue Proteins ,Biology ,Striatum ,medicine ,Animals ,Humans ,Gene ,[ SDV ] Life Sciences [q-bio] ,medicine.disease ,Molecular biology ,Corpus Striatum ,Gene regulation ,Mice, Inbred C57BL ,Ageing ,Disease Models, Animal ,Gene Expression Regulation ,Mutation ,Neurology (clinical) ,Geriatrics and Gerontology ,Serine Proteases ,Developmental Biology - Abstract
International audience; A large number of gene products that are enriched in the striatum have ill-defined functions, although they may have key roles in age-dependent neurodegenerative diseases affecting the striatum, especially Huntington disease (HD). In the present study, we focused on Abhd11os, (called ABHD11-AS1 in human) which is a putative long noncoding RNA (lncRNA) whose expression is enriched in the mouse striatum. We confirm that despite the presence of 2 small open reading frames (ORFs) in its sequence, Abhd11os is not translated into a detectable peptide in living cells. We demonstrate that Abhd11os levels are markedly reduced in different mouse models of HD. We performed in vivo experiments in mice using lentiviral vectors encoding either Abhd11os or a small hairpin RNA targeting Abhd11os. Results show that Abhd11os overexpression produces neuroprotection against an N-terminal fragment of mutant huntingtin, whereas Abhd11os knockdown is protoxic. These novel results indicate that the loss lncRNA Abhd11os likely contribute to striatal vulnerability in HD. Our study emphasizes that lncRNA may play crucial roles in neurodegenerative diseases. more...
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- 2015
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15. Possible involvement of self-defense mechanisms in the preferential vulnerability of the striatum in Huntington's disease
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Emmanuel Brouillet, Laetitia Francelle, Laurie Galvan, Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Center for Neurobehavioral Genetics, Semel Institute, University of California, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), University of California (UC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) more...
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Huntingtin ,Huntington ,striatum ,Excitotoxicity ,markers ,Review Article ,Striatum ,Biology ,medicine.disease_cause ,Neuroprotection ,lcsh:RC321-571 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Huntington's disease ,medicine ,Receptor ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,ComputingMilieux_MISCELLANEOUS ,RGS2 ,030304 developmental biology ,0303 health sciences ,gene products ,medicine.disease ,cell death ,nervous system ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,signaling ,Trinucleotide repeat expansion ,excitotoxicity ,Neuroscience ,030217 neurology & neurosurgery - Abstract
HD is caused by a mutation in the huntingtin gene that consists in a CAG repeat expansion translated into an abnormal poly-glutamine (polyQ) tract in the huntingtin (Htt) protein. The most striking neuropathological finding in HD is the atrophy of the striatum. The regional expression of mutant Htt (mHtt) is ubiquitous in the brain and cannot explain by itself the preferential vulnerability of the striatum in HD. mHtt has been shown to produce an early defect in transcription, through direct alteration of the function of key regulators of transcription and in addition, more indirectly, as a result of compensatory responses to cellular stress. In this review, we focus on gene products that are preferentially expressed in the striatum and have down- or up-regulated expression in HD and, as such, may play a crucial role in the susceptibility of the striatum to mHtt. Many of these striatal gene products are for a vast majority down-regulated and more rarely increased in HD. Recent research shows that some of these striatal markers have a pro-survival/neuroprotective role in neurons (e.g., MSK1, A2A, and CB1 receptors) whereas others enhance the susceptibility of striatal neurons to mHtt (e.g., Rhes, RGS2, D2 receptors). The down-regulation of these latter proteins may be considered as a potential self-defense mechanism to slow degeneration. For a majority of the striatal gene products that have been identified so far, their function in the striatum is unknown and their modifying effects on mHtt toxicity remain to be experimentally addressed. Focusing on these striatal markers may contribute to a better understanding of HD pathogenesis, and possibly the identification of novel therapeutic targets. more...
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- 2014
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16. A role of mitochondrial complex II defects in genetic models of Huntington's disease expressing N-terminal fragments of mutant huntingtin
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Josep M. Canals, Noelle Dufour, Philippe Hantraye, Diane Houitte, Martine Guillermier, Maria Damiano, Jordi Alberch, Fanny Petit, Emmanuel Brouillet, M. Flint Beal, Marilena D'Aurelio, Laurie Galvan, Elsa Diguet, Nicole Déglon, Carole Malgorn, Thierry Delzescaux, Lucile Benhaim, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Weill Medical College of Cornell University [New York], Institut d'Imagerie BioMédicale (I2BM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Center for Neurobehavioral Genetics, Semel Institute, University of California (UC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Department of Neurology and Neuroscience, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), and University of California more...
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Male ,Huntingtin ,Protein subunit ,Mice, Transgenic ,Nerve Tissue Proteins ,Biology ,Mitochondrion ,medicine.disease_cause ,Neuroprotection ,Mitochondrial Proteins ,Rats, Sprague-Dawley ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Huntington's disease ,Genetic model ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Genetics (clinical) ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Neurons ,0303 health sciences ,Mutation ,Huntingtin Protein ,Electron Transport Complex II ,Articles ,General Medicine ,Polyglutamine tract ,medicine.disease ,Molecular biology ,Corpus Striatum ,3. Good health ,Mitochondria ,Rats ,Disease Models, Animal ,Huntington Disease ,Female ,Mutant Proteins ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,030217 neurology & neurosurgery - Abstract
Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat encoding a polyglutamine tract in the huntingtin (Htt) protein. The mutation leads to neuronal death through mechanisms which are still unknown. One hypothesis is that mitochondrial defects may play a key role. In support of this, the activity of mitochondrial complex II (C-II) is preferentially reduced in the striatum of HD patients. Here, we studied C-II expression in different genetic models of HD expressing N-terminal fragments of mutant Htt (mHtt). Western blot analysis showed that the expression of the 30 kDa Iron–Sulfur (Ip) subunit of C-II was significantly reduced in the striatum of the R6/1 transgenic mice, while the levels of the FAD containing catalytic 70 kDa subunit (Fp) were not significantly changed. Blue native gel analysis showed that the assembly of C-II in mitochondria was altered early in N171-82Q transgenic mice. Early loco-regional reduction in C-II activity and Ip protein expression was also demonstrated in a rat model of HD using intrastriatal injection of lentiviral vectors encoding mHtt. Infection of the rat striatum with a lentiviral vector coding the C-II Ip or Fp subunits induced a significant overexpression of these proteins that led to significant neuroprotection of striatal neurons against mHtt neurotoxicity. These results obtained in vivo support the hypothesis that structural and functional alterations of C-II induced by mHtt may play a critical role in the degeneration of striatal neurons in HD and that mitochondrial-targeted therapies may be useful in its treatment. more...
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- 2013
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17. Multiple Sources of Striatal Inhibition Are Differentially Affected in Huntington’s Disease Mouse Models
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Michael Levine, Karl Deisseroth, Véronique M. André, Elian P. Botelho, Jane Y. Chen, Joseph B. Watson, Shilpa P. Rao, Carlos Cepeda, Laurie Galvan, Sandra M. Holley, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB) more...
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Genetically modified mouse ,Male ,Neural Inhibition ,Action Potentials ,Stimulation ,Mice, Transgenic ,Optogenetics ,Biology ,Indirect pathway of movement ,Inhibitory postsynaptic potential ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Huntington's disease ,medicine ,Animals ,Humans ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,General Neuroscience ,medicine.disease ,Corpus Striatum ,Mice, Inbred C57BL ,Electrophysiology ,Disease Models, Animal ,Huntington Disease ,nervous system ,Mice, Inbred CBA ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Female ,Neuroscience ,030217 neurology & neurosurgery - Abstract
In Huntington's disease (HD) mouse models, spontaneous inhibitory synaptic activity is enhanced in a subpopulation of medium-sized spiny neurons (MSNs), which could dampen striatal output. We examined the potential source(s) of increased inhibition using electrophysiological and optogenetic methods to assess feedback and feedforward inhibition in two transgenic mouse models of HD. Single whole-cell patch-clamp recordings demonstrated that increased GABA synaptic activity impinges principally on indirect pathway MSNs. Dual patch recordings between MSNs demonstrated reduced connectivity between MSNs in HD mice. However, while connectivity was strictly unidirectional in controls, in HD mice bidirectional connectivity occurred. Other sources of increased GABA activity in MSNs also were identified. Dual patch recordings from fast spiking (FS) interneuron–MSN pairs demonstrated greater but variable amplitude responses in MSNs. In agreement, selective optogenetic stimulation of parvalbumin-expressing, FS interneurons induced significantly larger amplitude MSN responses in HD compared with control mice. While there were no differences in responses of MSNs evoked by activating single persistent low-threshold spiking (PLTS) interneurons in recorded pairs, these interneurons fired more action potentials in both HD models, providing another source for increased frequency of spontaneous GABA synaptic activity in MSNs. Selective optogenetic stimulation of somatostatin-expressing, PLTS interneurons did not reveal any significant differences in responses of MSNs in HD mice. These findings provide strong evidence that both feedforward and to a lesser extent feedback inhibition to MSNs in HD can potentially be sources for the increased GABA synaptic activity of indirect pathway MSNs. more...
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- 2013
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18. Effects of the Pimelic Diphenylamide Histone Deacetylase Inhibitor HDACi 4b on the R6/2 and N171-82Q Mouse Models of Huntington's Disease
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Michael Levine, Prasad R. Joshi, Carlos Cepeda, Laurie Galvan, My N. Huynh, Elizabeth A. Wang, and Jane Y. Chen
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Drug ,business.industry ,medicine.drug_class ,Transgene ,media_common.quotation_subject ,Histone deacetylase inhibitor ,Correction ,Medicine (miscellaneous) ,Disease ,Pharmacology ,Preclinical Therapeutics ,medicine.disease ,Bioinformatics ,Phenotype ,Huntington's disease ,HDAC inhibitor ,Medicine ,Histone deacetylase ,business ,media_common - Abstract
This report represents a detailed description of experiments designed to replicate and extend the findings of a published study on the effects of treating the R6/2 Huntington’s disease (HD) mouse model with ~300 CAG repeats using the pimelic diphenylamide histone deacetylase (HDAC) inhibitor, HDACi 4b (Thomas et al., 2008). In addition to testing the R6/2 mice, similar experiments examined the effects of the drug on a second transgenic HD mouse model, the N171-82Q mice. As in the original study, the drug was delivered in the drinking water. In the present study we tested larger groups of mice than in the original study. The results indicated that we were unable to replicate the significant behavioral effects of oral HDACi 4b treatment in the R6/2 mice. There were however, non-significant trends for the treated R6/2 mice to be less affected on some of the measures and there were instances of phenotype progression being delayed in these treated mice. In contrast, we did replicate the protection from striatal atrophy in the R6/2 mice. We also did not observe any beneficial effects of HDACi 4b treatment in the N171-82Q mice. Although the behavioral procedures were replicated and an automated activity assessment was added, there were several unexpected complications in terms of solubility of the drug, CAG repeat length differences and gender differences in progression of the phenotype that could have affected outcomes. Clearly more studies will have to be performed using other methods of delivery as well as assessing effects in more slowly progressing HD models to better evaluate the effects of this HDAC inhibitor. more...
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- 2013
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19. Functional Differences Between Direct and Indirect Striatal Output Pathways in Huntington's Disease
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Carlos Cepeda, Elizabeth A. Wang, Michael Levine, Véronique M. André, Laurie Galvan, Center for Neurobehavioral Genetics, Semel Institute, University of California, Department of Statistics [West Lafayette], and Purdue University [West Lafayette] more...
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Dopamine ,Mice, Transgenic ,Neurotransmission ,Optogenetics ,Biology ,Indirect pathway of movement ,Inhibitory postsynaptic potential ,Synaptic Transmission ,Article ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Huntington's disease ,Neural Pathways ,medicine ,Animals ,Humans ,Direct pathway of movement ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Neurons ,0303 health sciences ,medicine.disease ,Corpus Striatum ,Disease Models, Animal ,Huntington Disease ,Excitatory postsynaptic potential ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neurology (clinical) ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
There is morphological evidence for differential alterations in striatal medium-sized spiny neurons (MSNs) giving rise to the direct and indirect output pathways in Huntington’s disease (HD). MSNs of the indirect pathway appear to be particularly vulnerable and markers for these neurons are lost early in postmortem brains and in genetic mouse models. In contrast, MSNs of the direct pathway appear to be relatively spared in the early stages. Because of the great morphological and electrophysiological similarities between MSNs of these pathways, until recently it was difficult to tease apart their functional alterations in HD models. The recent use of the enhanced green fluorescent protein gene as a reporter to identify dopamine D1 (direct pathway) and D2 (indirect pathway) receptor-expressing MSNs has made it possible to examine synaptic function in each pathway. The outcomes of such studies demonstrate significant time-dependent changes in the balance of excitatory and inhibitory inputs to both direct and indirect pathway MSNs in HD and emphasize early increases in both excitatory and inhibitory inputs to direct pathway MSNs. There also is a strong influence of alterations in dopamine modulation that possibly cause some of the changes in excitatory and inhibitory synaptic transmission in the HD models. These changes will markedly alter the output structures, the GPi and the SNr. In the future, the use of combined optogenetics with identified neurons in each pathway will help unravel the next set of questions about how the output nuclei are affected in HD. more...
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- 2012
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20. Capucin does not modify the toxicity of a mutant Huntingtin fragment in vivo
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Diane Houitte, Laurie Galvan, Matthieu Gérard, Martine Guillermier, Fanny Petit, Marie-Claude Gaillard, Jean-Marc Elalouf, Nicole Déglon, Nad'a Lepejová, Patrick Héry, Gilles Bonvento, Noelle Dufour, Michel de Chaldée, Emmanuel Brouillet, Carole Malgorn, Center for Neurobehavioral Genetics, Semel Institute, University of California, Service de Biologie Intégrative et Génétique Moléculaire (SBIGeM), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, DBJC-SBMS, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche du CEA/DSV/iBiTec-S/SIMOPRO, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institut d'Imagerie BioMédicale (I2BM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of California (UC), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA) more...
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Aging ,Huntingtin ,Nerve Tissue Proteins ,Striatum ,Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Huntington's disease ,Basal ganglia ,medicine ,Huntingtin Protein ,Animals ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,General Neuroscience ,Neurodegeneration ,Neurotoxicity ,Membrane Proteins ,Nuclear Proteins ,medicine.disease ,Molecular biology ,Corpus Striatum ,nervous system ,Knockout mouse ,Mutation ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neurology (clinical) ,Geriatrics and Gerontology ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Genes selectively expressed in the striatum may be involved in the preferential vulnerability of striatal neurons to Huntington's disease (HD). Here, we investigated whether perturbations of Capucin expression, which is enriched in the striatum and downregulated in Huntington's disease models, could modify the neurotoxicity induced by the injection of a lentiviral vector encoding a short N-terminal fragment of mutant Huntingtin (mHtt) into the mouse striatum. Neither constitutive Capucin deficiency in knockout mice nor lentiviral vector-mediated Capucin overexpression in the striatum of adult wild type mice significantly modified vulnerability to the mHtt fragment in vivo, suggesting that Capucin has no impact on mHtt toxicity. more...
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- 2011
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21. Hyposensitivity to the amnesic effects of scopolamine or amyloid β25–35 peptide in heterozygous acetylcholinesterase knockout (AChE+/−) mice
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Julie Espallergues, Laurence Lepourry, Laurie Galvan, Béatrice Bonafos, Tangui Maurice, Arnaud Chatonnet, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Center for Neurobehavioral Genetics, Semel Institute, University of California, Dynamique Musculaire et Métabolisme (DMEM), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université Montpellier 2 - Sciences et Techniques (UM2)-École pratique des hautes études (EPHE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de Physiologie Animale (INRA), Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL) more...
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Heterozygote ,medicine.medical_specialty ,Amyloid ,Aché ,Toxicology ,LEARNING AND MEMORY ,AMYLOID PEPTIDE ,ACETYLCHOLINESTERASE ,APPRENTISSAGE ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Muscarinic acetylcholine receptor ,medicine ,Animals ,SCOPOLAMINE ,Maze Learning ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,FORCED SWIMMING ,Antagonist ,General Medicine ,Acetylcholinesterase ,Peptide Fragments ,language.human_language ,3. Good health ,Endocrinology ,chemistry ,Knockout mouse ,Toxicity ,language ,Cholinergic ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Amnesia ,Peptides ,KNOCKOUT MOUSE ,030217 neurology & neurosurgery - Abstract
International audience; We examined the sensitivity of AChE(+/-) mice to the amnesic effects of scopolamine and amyloid peptide. AChE(+/-) and AChE(+/+) littermates, tested at 5-9 weeks of age, failed to show any difference in locomotion, exploration and anxiety in the open-field test, or in-place learning in the water-maze. However, when treated with the muscarinic receptor antagonist scopolamine (0.5, 5 mg/kg s.c.) 20 min before each water-maze training session, learning impairments were observed at both doses in AChE(+/+) mice, but only at the highest dose in AChE(+/-) mice. The central injection of A beta(25-35) peptide (9 nmol) induced learning deficits only in AChE(+/+) but not in AChE(+/-) mice. Therefore, the hyper-activity of cholinergic systems in AChE(+/-) mice did not result in increased memory abilities, but prevented the deleterious effects Of muscarinic blockade or amyloid toxicity. more...
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- 2008
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22. Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington’s Disease
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Prasad R. Joshi, My N. Huynh, Laurie Galvan, Carlos Cepeda, Michael S. Levine, Sandra M. Holley, Yvette E. Fisher, Anna Parievsky, and Jane Y. Chen
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Huntingtin ,striatum ,Striatum ,Biology ,Inhibitory postsynaptic potential ,GABA ,Huntington's disease ,medicine ,optogenetics ,cholinergic interneurons ,musculoskeletal, neural, and ocular physiology ,General Neuroscience ,General Medicine ,New Research ,medicine.disease ,Electrophysiology ,nervous system ,R6/2 mouse model ,Cholinergic ,GABAergic ,Disorders of the Nervous System ,Neuroscience ,Acetylcholine ,Huntington’s disease ,medicine.drug - Abstract
Although large cholinergic interneurons (LCIs) in striatum are spared in Huntington's disease (HD), deficits in cholinergic function have been described. Here we demonstrate in a mouse model of HD that the firing patterns of LCIs are disrupted and this is due to aberrant GABAergic neurotransmission. This explains cholinergic deficits in HD., In Huntington’s disease (HD), a hereditary neurodegenerative disorder, striatal medium-sized spiny neurons undergo degenerative changes. In contrast, large cholinergic interneurons (LCIs) are relatively spared. However, their ability to release acetylcholine (ACh) is impaired. The present experiments examined morphological and electrophysiological properties of LCIs in the R6/2 mouse model of HD. R6/2 mice show a severe, rapidly progressing phenotype. Immunocytochemical analysis of choline acetyltransferase-positive striatal neurons showed that, although the total number of cells was not changed, somatic areas were significantly smaller in symptomatic R6/2 mice compared to wild-type (WT) littermates, For electrophysiology, brain slices were obtained from presymptomatic (3-4 weeks) and symptomatic (>8 weeks) R6/2 mice and their WT littermates. Striatal LCIs were identified by somatic size and spontaneous action potential firing in the cell-attached mode. Passive and active membrane properties of LCIs were similar in presymptomatic R6/2 and WT mice. In contrast, LCIs from symptomatic R6/2 animals displayed smaller membrane capacitance and higher input resistance, consistent with reduced somatic size. In addition, more LCIs from symptomatic mice displayed irregular firing patterns and bursts of action potentials. They also displayed a higher frequency of spontaneous GABAergic IPSCs and larger amplitude of electrically evoked IPSCs. Selective optogenetic stimulation of somatostatin- but not parvalbumin-containing interneurons also evoked larger amplitude IPSCs in LCIs from R6/2 mice. In contrast, glutamatergic spontaneous or evoked postsynaptic currents were not affected. Morphological and electrophysiological alterations, in conjunction with the presence of mutant huntingtin in LCIs, could explain impaired ACh release in HD mouse models. more...
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- 2015
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23. JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in Mouse
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Daniel H. Geschwind, Changhoon Lee, Eric Tam, Elyse P. Kite, Stephanie A. White, Laurie Galvan, Carlos Cepeda, Jeremy A. Miller, Jason L. Stein, Jane Y. Chen, Zachary D. Burkett, Asami Oguro-Ando, Alvin Li, Jamee M. Berg, James A. Wohlschlegel, Leslie Chen, Mary E. Starks, Scott C. Fears, Ajay A. Vashisht, Olga Peñagarikano, Michael S. Levine, Amos Gdalyahu, Noor B. Al-Sharif, Department of Chemistry, North Carolina Raleigh, North Carolina State University [Raleigh] (NC State), University of North Carolina System (UNC)-University of North Carolina System (UNC), Center for Neurobehavioral Genetics, Semel Institute, and University of California more...
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Male ,Proteomics ,Autism Spectrum Disorder ,Autism ,Synaptogenesis ,RNA-binding protein ,Inbred C57BL ,Mice ,Neurodevelopmental disorder ,2.1 Biological and endogenous factors ,Psychology ,Gene Regulatory Networks ,ComputingMilieux_MISCELLANEOUS ,Pediatric ,Mice, Knockout ,Neurons ,General Neuroscience ,musculoskeletal, neural, and ocular physiology ,Adaptor Proteins ,RNA-Binding Proteins ,Translation (biology) ,Fragile X syndrome ,Mental Health ,Autism spectrum disorder ,Neurological ,Cognitive Sciences ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neural development ,psychological phenomena and processes ,Knockout ,Neuroscience(all) ,Biology ,behavioral disciplines and activities ,Rare Diseases ,Behavioral and Social Science ,mental disorders ,Genetics ,medicine ,Animals ,Intellectual and Developmental Disabilities ,Adaptor Proteins, Signal Transducing ,Neurology & Neurosurgery ,Signal Transducing ,Neurosciences ,medicine.disease ,Brain Disorders ,Mice, Inbred C57BL ,nervous system ,Fragile X Syndrome ,Protein Biosynthesis ,Synapses ,Janus kinase ,Neuroscience - Abstract
© 2015 Elsevier Inc. Autism spectrum disorder (ASD) is a heritable, common neurodevelopmental disorder with diverse genetic causes. Several studies have implicated protein synthesis as one among several of its potential convergent mechanisms. We originally identified Janus kinase and microtubule-interacting protein 1 (JAKMIP1) as differentially expressed in patients with distinct syndromic forms of ASD, fragile X syndrome, and 15q duplication syndrome. Here, we provide multiple lines of evidence that JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes fragile X mental retardation protein, DEAD box helicase 5, and the poly(A) binding protein cytoplasmic 1. JAKMIP1 loss dysregulates neuronal translation during synaptic development, affecting glutamatergic NMDAR signaling, and results in social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors in the mouse. These findings define an important and novel role for JAKMIP1 in neural development and further highlight pathways regulating mRNA translation during synaptogenesis in the genesis of neurodevelopmental disorders. more...
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