Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety / Tori L. SCHAEFER in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.6 Titre : Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety Type de document : texte imprimé Auteurs : Tori L. SCHAEFER, Auteur ; Matthew H. DAVENPORT, Auteur ; Lindsay M. GRAINGER, Auteur ; Chandler K. ROBINSON, Auteur ; Anthony T. EARNHEART, Auteur ; Melinda S. STEGMAN, Auteur ; Anna L. LANG, Auteur ; Amy A. ASHWORTH, Auteur ; Gemma MOLINARO, Auteur ; Kimberly M. HUBER, Auteur ; Craig ERICKSON, Auteur Article en page(s) : p.6 Langues : Anglais (eng) Mots-clés : Anxiety  Dendritic spine density  Electrophysiology  Extracellular signal-related kinase  Fragile X syndrome  Hippocampus  Hyperactivity  Open field  Striatum Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X Syndrome (FXS) occurs as a result of a silenced fragile X mental retardation 1 gene (FMR1) and subsequent loss of fragile X mental retardation protein (FMRP) expression. Loss of FMRP alters excitatory/inhibitory signaling balance, leading to increased neuronal hyperexcitability and altered behavior. Acamprosate (the calcium salt of N-acetylhomotaurinate), a drug FDA-approved for relapse prevention in the treatment of alcohol dependence in adults, is a novel agent with multiple mechanisms that may be beneficial for people with FXS. There are questions regarding the neuroactive effects of acamprosate and the significance of the molecule's calcium moiety. Therefore, the electrophysiological, cellular, molecular, and behavioral effects of acamprosate were assessed in the Fmr1(-/y) (knock out; KO) mouse model of FXS controlling for the calcium salt in several experiments. METHODS: Fmr1 KO mice and their wild-type (WT) littermates were utilized to assess acamprosate treatment on cortical UP state parameters, dendritic spine density, and seizure susceptibility. Brain extracellular-signal regulated kinase 1/2 (ERK1/2) activation was used to investigate this signaling molecule as a potential biomarker for treatment response. Additional adult mice were used to assess chronic acamprosate treatment and any potential effects of the calcium moiety using CaCl2 treatment on behavior and nuclear ERK1/2 activation. RESULTS: Acamprosate attenuated prolonged cortical UP state duration, decreased elevated ERK1/2 activation in brain tissue, and reduced nuclear ERK1/2 activation in the dentate gyrus in KO mice. Acamprosate treatment modified behavior in anxiety and locomotor tests in Fmr1 KO mice in which control-treated KO mice were shown to deviate from control-treated WT mice. Mice treated with CaCl2 were not different from saline-treated mice in the adult behavior battery or nuclear ERK1/2 activation. CONCLUSIONS: These data indicate that acamprosate, and not calcium, improves function reminiscent of reduced anxiety-like behavior and hyperactivity in Fmr1 KO mice and that acamprosate attenuates select electrophysiological and molecular dysregulation that may play a role in the pathophysiology of FXS. Differences between control-treated KO and WT mice were not evident in a recognition memory test or in examination of acoustic startle response/prepulse inhibition which impeded conclusions from being made about the treatment effects of acamprosate in these instances. En ligne : http://dx.doi.org/10.1186/s11689-017-9184-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349 [article] Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety [texte imprimé] / Tori L. SCHAEFER, Auteur ; Matthew H. DAVENPORT, Auteur ; Lindsay M. GRAINGER, Auteur ; Chandler K. ROBINSON, Auteur ; Anthony T. EARNHEART, Auteur ; Melinda S. STEGMAN, Auteur ; Anna L. LANG, Auteur ; Amy A. ASHWORTH, Auteur ; Gemma MOLINARO, Auteur ; Kimberly M. HUBER, Auteur ; Craig ERICKSON, Auteur . - p.6. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.6 Mots-clés : Anxiety  Dendritic spine density  Electrophysiology  Extracellular signal-related kinase  Fragile X syndrome  Hippocampus  Hyperactivity  Open field  Striatum Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X Syndrome (FXS) occurs as a result of a silenced fragile X mental retardation 1 gene (FMR1) and subsequent loss of fragile X mental retardation protein (FMRP) expression. Loss of FMRP alters excitatory/inhibitory signaling balance, leading to increased neuronal hyperexcitability and altered behavior. Acamprosate (the calcium salt of N-acetylhomotaurinate), a drug FDA-approved for relapse prevention in the treatment of alcohol dependence in adults, is a novel agent with multiple mechanisms that may be beneficial for people with FXS. There are questions regarding the neuroactive effects of acamprosate and the significance of the molecule's calcium moiety. Therefore, the electrophysiological, cellular, molecular, and behavioral effects of acamprosate were assessed in the Fmr1(-/y) (knock out; KO) mouse model of FXS controlling for the calcium salt in several experiments. METHODS: Fmr1 KO mice and their wild-type (WT) littermates were utilized to assess acamprosate treatment on cortical UP state parameters, dendritic spine density, and seizure susceptibility. Brain extracellular-signal regulated kinase 1/2 (ERK1/2) activation was used to investigate this signaling molecule as a potential biomarker for treatment response. Additional adult mice were used to assess chronic acamprosate treatment and any potential effects of the calcium moiety using CaCl2 treatment on behavior and nuclear ERK1/2 activation. RESULTS: Acamprosate attenuated prolonged cortical UP state duration, decreased elevated ERK1/2 activation in brain tissue, and reduced nuclear ERK1/2 activation in the dentate gyrus in KO mice. Acamprosate treatment modified behavior in anxiety and locomotor tests in Fmr1 KO mice in which control-treated KO mice were shown to deviate from control-treated WT mice. Mice treated with CaCl2 were not different from saline-treated mice in the adult behavior battery or nuclear ERK1/2 activation. CONCLUSIONS: These data indicate that acamprosate, and not calcium, improves function reminiscent of reduced anxiety-like behavior and hyperactivity in Fmr1 KO mice and that acamprosate attenuates select electrophysiological and molecular dysregulation that may play a role in the pathophysiology of FXS. Differences between control-treated KO and WT mice were not evident in a recognition memory test or in examination of acoustic startle response/prepulse inhibition which impeded conclusions from being made about the treatment effects of acamprosate in these instances. En ligne : http://dx.doi.org/10.1186/s11689-017-9184-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349

Ribosome profiling in mouse hippocampus: plasticity-induced regulation and bidirectional control by TSC2 and FMRP / Annie HIEN in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 78 p. Titre : Ribosome profiling in mouse hippocampus: plasticity-induced regulation and bidirectional control by TSC2 and FMRP Type de document : texte imprimé Auteurs : Annie HIEN, Auteur ; Gemma MOLINARO, Auteur ; Botao LIU, Auteur ; Kimberly M. HUBER, Auteur ; Joel D. RICHTER, Auteur Article en page(s) : 78 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in TSC2 are the most common cause of tuberous sclerosis (TSC), a disorder with a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required for group 1 metabotropic glutamate receptor-dependent synaptic long-term depression (mGluR-LTD) and behavior, but the identity of mRNAs responsive to mGluR-LTD signaling is largely unknown. METHODS: We utilized Tsc2(+/-) mice as a mouse model of TSC and prepared hippocampal slices from these animals. We induced mGluR-LTD synaptic plasticity in slices and processed the samples for RNA-seq and ribosome profiling to identify differentially expressed genes in Tsc2(+/-) and following mGluR-LTD synaptic plasticity. RESULTS: Ribosome profiling reveals that in Tsc2(+/-) mouse hippocampal slices, the expression of several mRNAs was dysregulated: terminal oligopyrimidine (TOP)-containing mRNAs decreased, while FMRP-binding targets increased. Remarkably, we observed the opposite changes of FMRP binding targets in Fmr1(-/y) hippocampi. In wild-type hippocampus, induction of mGluR-LTD caused rapid changes in the steady-state levels of hundreds of mRNAs, many of which are FMRP targets. Moreover, mGluR-LTD failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in TSC mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in TSC mice. CONCLUSION: These results suggest a molecular basis for bidirectional regulation of synaptic plasticity and behavior by TSC2 and FMRP. Our study also suggests that altered mGluR-regulated translation elongation contributes to impaired synaptic plasticity in Tsc2(+/-) mice. En ligne : http://dx.doi.org/10.1186/s13229-020-00384-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Ribosome profiling in mouse hippocampus: plasticity-induced regulation and bidirectional control by TSC2 and FMRP [texte imprimé] / Annie HIEN, Auteur ; Gemma MOLINARO, Auteur ; Botao LIU, Auteur ; Kimberly M. HUBER, Auteur ; Joel D. RICHTER, Auteur . - 78 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 78 p. Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in TSC2 are the most common cause of tuberous sclerosis (TSC), a disorder with a high incidence of autism and intellectual disability. TSC2 regulates mRNA translation required for group 1 metabotropic glutamate receptor-dependent synaptic long-term depression (mGluR-LTD) and behavior, but the identity of mRNAs responsive to mGluR-LTD signaling is largely unknown. METHODS: We utilized Tsc2(+/-) mice as a mouse model of TSC and prepared hippocampal slices from these animals. We induced mGluR-LTD synaptic plasticity in slices and processed the samples for RNA-seq and ribosome profiling to identify differentially expressed genes in Tsc2(+/-) and following mGluR-LTD synaptic plasticity. RESULTS: Ribosome profiling reveals that in Tsc2(+/-) mouse hippocampal slices, the expression of several mRNAs was dysregulated: terminal oligopyrimidine (TOP)-containing mRNAs decreased, while FMRP-binding targets increased. Remarkably, we observed the opposite changes of FMRP binding targets in Fmr1(-/y) hippocampi. In wild-type hippocampus, induction of mGluR-LTD caused rapid changes in the steady-state levels of hundreds of mRNAs, many of which are FMRP targets. Moreover, mGluR-LTD failed to promote phosphorylation of eukaryotic elongation factor 2 (eEF2) in TSC mice, and chemically mimicking phospho-eEF2 with low cycloheximide enhances mGluR-LTD in TSC mice. CONCLUSION: These results suggest a molecular basis for bidirectional regulation of synaptic plasticity and behavior by TSC2 and FMRP. Our study also suggests that altered mGluR-regulated translation elongation contributes to impaired synaptic plasticity in Tsc2(+/-) mice. En ligne : http://dx.doi.org/10.1186/s13229-020-00384-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

The E3 Ubiquitin Ligase UBE3B Regulates Synaptic Development and Cortical Network Activity / Shayal VASHISTH in Autism Research, 19-5 (May 2026)  

Public ISBD [article]  inAutism Research > 19-5 (May 2026) . - p.e70229 Titre : The E3 Ubiquitin Ligase UBE3B Regulates Synaptic Development and Cortical Network Activity Type de document : texte imprimé Auteurs : Shayal VASHISTH, Auteur ; Aleya SHEDD, Auteur ; Ariel AIKEN, Auteur ; Solmi CHEON, Auteur ; Josh BANDOPADHAY, Auteur ; Kiran KAUR, Auteur ; Kimberly M. HUBER, Auteur ; Maria H. CHAHROUR, Auteur Article en page(s) : p.e70229 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : ABSTRACT Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired communication, abnormal social interactions, and restricted, repetitive behaviors. Pathogenic mutations in UBE3B result in neurodevelopmental disease, including intellectual disability, lack of speech, and ASD. UBE3B is an E3 ubiquitin ligase that tags substrate proteins with ubiquitin, marking them for proteasomal degradation. The ubiquitin-proteasome system (UPS) regulates several signaling pathways critical for neurodevelopment, including neurogenesis and synaptogenesis, and mutations in various UPS genes have been identified in ASD and related neurodevelopmental disorders. To investigate the function of UBE3B in the brain and how its disruption gives rise to neurodevelopmental abnormalities, we generated a central nervous system-specific conditional Ube3b knockout (cKO) mouse model and evaluated the resulting neurobehavioral phenotypes. We found that Ube3b cKO mice exhibit severe deficits in vocalization, social behavior, learning and memory, and motor skills. Assessment of in vivo neuronal phenotypes revealed defects in dendritic morphogenesis, reduced excitatory synapse density, diminished spontaneous cortical circuit activity, decreased AMPA receptor surface expression, and hyperexcitability of excitatory cortical neurons. Using quantitative proteomics, we profiled the proteome and ubiquitome of neural stem cells and identified 116 proteins that exhibited increased protein levels and reduced ubiquitination following loss of UBE3B. These proteins were highly enriched for ones involved in synaptic processes, and we confirmed interaction of UBE3B with several key synaptic proteins, including ATP1A1, DOCK7, NLGN2, and STX12. Collectively, our findings identify a role for UBE3B in regulating social, cognitive, and motor functions, and neuronal morphogenesis and activity by fine-tuning the synaptic proteome. En ligne : https://doi.org/10.1002/aur.70229 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=587 [article] The E3 Ubiquitin Ligase UBE3B Regulates Synaptic Development and Cortical Network Activity [texte imprimé] / Shayal VASHISTH, Auteur ; Aleya SHEDD, Auteur ; Ariel AIKEN, Auteur ; Solmi CHEON, Auteur ; Josh BANDOPADHAY, Auteur ; Kiran KAUR, Auteur ; Kimberly M. HUBER, Auteur ; Maria H. CHAHROUR, Auteur . - p.e70229. Langues : Anglais (eng) in Autism Research > 19-5 (May 2026) . - p.e70229 Index. décimale : PER Périodiques Résumé : ABSTRACT Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired communication, abnormal social interactions, and restricted, repetitive behaviors. Pathogenic mutations in UBE3B result in neurodevelopmental disease, including intellectual disability, lack of speech, and ASD. UBE3B is an E3 ubiquitin ligase that tags substrate proteins with ubiquitin, marking them for proteasomal degradation. The ubiquitin-proteasome system (UPS) regulates several signaling pathways critical for neurodevelopment, including neurogenesis and synaptogenesis, and mutations in various UPS genes have been identified in ASD and related neurodevelopmental disorders. To investigate the function of UBE3B in the brain and how its disruption gives rise to neurodevelopmental abnormalities, we generated a central nervous system-specific conditional Ube3b knockout (cKO) mouse model and evaluated the resulting neurobehavioral phenotypes. We found that Ube3b cKO mice exhibit severe deficits in vocalization, social behavior, learning and memory, and motor skills. Assessment of in vivo neuronal phenotypes revealed defects in dendritic morphogenesis, reduced excitatory synapse density, diminished spontaneous cortical circuit activity, decreased AMPA receptor surface expression, and hyperexcitability of excitatory cortical neurons. Using quantitative proteomics, we profiled the proteome and ubiquitome of neural stem cells and identified 116 proteins that exhibited increased protein levels and reduced ubiquitination following loss of UBE3B. These proteins were highly enriched for ones involved in synaptic processes, and we confirmed interaction of UBE3B with several key synaptic proteins, including ATP1A1, DOCK7, NLGN2, and STX12. Collectively, our findings identify a role for UBE3B in regulating social, cognitive, and motor functions, and neuronal morphogenesis and activity by fine-tuning the synaptic proteome. En ligne : https://doi.org/10.1002/aur.70229 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=587

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