Acamprosate in a mouse model of fragile X syndrome: modulation of spontaneous cortical activity, ERK1/2 activation, locomotor behavior, and anxiety / T. 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 et/ou numérique Auteurs : T. L. SCHAEFER, Auteur ; M. H. DAVENPORT, Auteur ; L. M. GRAINGER, Auteur ; C. K. ROBINSON, Auteur ; A. T. EARNHEART, Auteur ; M. S. STEGMAN, Auteur ; A. L. LANG, Auteur ; A. ASHWORTH, Auteur ; G. MOLINARO, Auteur ; K. M. HUBER, Auteur ; C. A. 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 et/ou numérique] / T. L. SCHAEFER, Auteur ; M. H. DAVENPORT, Auteur ; L. M. GRAINGER, Auteur ; C. K. ROBINSON, Auteur ; A. T. EARNHEART, Auteur ; M. S. STEGMAN, Auteur ; A. L. LANG, Auteur ; A. ASHWORTH, Auteur ; G. MOLINARO, Auteur ; K. M. HUBER, Auteur ; C. A. 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

d-Cycloserine enhances durability of social skills training in autism spectrum disorder / L. K. WINK in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 2p. Titre : d-Cycloserine enhances durability of social skills training in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : L. K. WINK, Auteur ; N. F. MINSHAWI, Auteur ; R. C. SHAFFER, Auteur ; M. H. PLAWECKI, Auteur ; D. J. POSEY, Auteur ; P. S. HORN, Auteur ; R. ADAMS, Auteur ; Ernest V. PEDAPATI, Auteur ; T. L. SCHAEFER, Auteur ; C. J. MCDOUGLE, Auteur ; N. B. SWIEZY, Auteur ; C. A. ERICKSON, Auteur Article en page(s) : 2p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/*drug therapy/psychology  Child  Child, Preschool  Cycloserine/*administration & dosage/pharmacology  Double-Blind Method  Drug Administration Schedule  Female  Humans  Learning/*drug effects  Male  Severity of Illness Index  Social Behavior  Treatment Outcome  *Autism  *Autism spectrum disorder  *Social skills training  *d-Cycloserine Index. décimale : PER Périodiques Résumé : BACKGROUND: d-Cycloserine (DCS) enhances extinction learning across species, but it has proven challenging to identify consistent benefit of DCS when added to therapeutic interventions. We conducted a placebo-controlled trial of DCS to potentiate social skills training in autism spectrum disorder (ASD) but found substantial improvement in both the DCS and placebo groups at the conclusion of active treatment. Here, we assess the impact of DCS 11 weeks following active treatment to evaluate the impact of DCS on treatment response durability. METHODS: Study participants included 60 outpatient youth with ASD, ages 5-11 years, all with IQ above 70, and significantly impaired social functioning who completed a 10-week active treatment phase during which they received weekly single doses of 50 mg of DCS or placebo administered 30 min prior to group social skills training. Following the 10-week active treatment phase, blinded follow-up assessments occurred at week 11 and week 22. The primary outcome measure for our durability of treatment evaluation was the parent-rated social responsiveness scale (SRS) total raw score at week 22. RESULTS: Analysis of the SRS total raw score demonstrated significant decrease for the DCS group compared to the placebo group (p = 0.042) indicating greater maintenance of treatment effect in the DCS group. DCS was well tolerated, with irritability being the most frequently reported adverse effect in both groups. CONCLUSIONS: The findings of this study suggest that DCS may help youth with ASD to maintain skills gained during sort-term social skills training. Larger-scale studies with longer follow-up will be necessary to further understand the long-term impact of DCS paired with structured social skills training. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01086475. En ligne : http://dx.doi.org/10.1186/s13229-017-0116-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] d-Cycloserine enhances durability of social skills training in autism spectrum disorder [Texte imprimé et/ou numérique] / L. K. WINK, Auteur ; N. F. MINSHAWI, Auteur ; R. C. SHAFFER, Auteur ; M. H. PLAWECKI, Auteur ; D. J. POSEY, Auteur ; P. S. HORN, Auteur ; R. ADAMS, Auteur ; Ernest V. PEDAPATI, Auteur ; T. L. SCHAEFER, Auteur ; C. J. MCDOUGLE, Auteur ; N. B. SWIEZY, Auteur ; C. A. ERICKSON, Auteur . - 2p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 2p. Mots-clés : Autism Spectrum Disorder/*drug therapy/psychology  Child  Child, Preschool  Cycloserine/*administration & dosage/pharmacology  Double-Blind Method  Drug Administration Schedule  Female  Humans  Learning/*drug effects  Male  Severity of Illness Index  Social Behavior  Treatment Outcome  *Autism  *Autism spectrum disorder  *Social skills training  *d-Cycloserine Index. décimale : PER Périodiques Résumé : BACKGROUND: d-Cycloserine (DCS) enhances extinction learning across species, but it has proven challenging to identify consistent benefit of DCS when added to therapeutic interventions. We conducted a placebo-controlled trial of DCS to potentiate social skills training in autism spectrum disorder (ASD) but found substantial improvement in both the DCS and placebo groups at the conclusion of active treatment. Here, we assess the impact of DCS 11 weeks following active treatment to evaluate the impact of DCS on treatment response durability. METHODS: Study participants included 60 outpatient youth with ASD, ages 5-11 years, all with IQ above 70, and significantly impaired social functioning who completed a 10-week active treatment phase during which they received weekly single doses of 50 mg of DCS or placebo administered 30 min prior to group social skills training. Following the 10-week active treatment phase, blinded follow-up assessments occurred at week 11 and week 22. The primary outcome measure for our durability of treatment evaluation was the parent-rated social responsiveness scale (SRS) total raw score at week 22. RESULTS: Analysis of the SRS total raw score demonstrated significant decrease for the DCS group compared to the placebo group (p = 0.042) indicating greater maintenance of treatment effect in the DCS group. DCS was well tolerated, with irritability being the most frequently reported adverse effect in both groups. CONCLUSIONS: The findings of this study suggest that DCS may help youth with ASD to maintain skills gained during sort-term social skills training. Larger-scale studies with longer follow-up will be necessary to further understand the long-term impact of DCS paired with structured social skills training. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01086475. En ligne : http://dx.doi.org/10.1186/s13229-017-0116-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Fragile X targeted pharmacotherapy: lessons learned and future directions / C. A. ERICKSON in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.7 Titre : Fragile X targeted pharmacotherapy: lessons learned and future directions Type de document : Texte imprimé et/ou numérique Auteurs : C. A. ERICKSON, Auteur ; M. H. DAVENPORT, Auteur ; T. L. SCHAEFER, Auteur ; L. K. WINK, Auteur ; Ernest V. PEDAPATI, Auteur ; J. A. SWEENEY, Auteur ; S. E. FITZPATRICK, Auteur ; W. Ted BROWN, Auteur ; Dejan B. BUDIMIROVIC, Auteur ; Randi J. HAGERMAN, Auteur ; D. HESSL, Auteur ; W. E. KAUFMANN, Auteur ; Elizabeth BERRY-KRAVIS, Auteur Article en page(s) : p.7 Langues : Anglais (eng) Mots-clés : Drug development  Fragile X syndrome  Genetic disorder  Targeted treatments  Translational treatment Index. décimale : PER Périodiques Résumé : Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts. En ligne : http://dx.doi.org/10.1186/s11689-017-9186-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349 [article] Fragile X targeted pharmacotherapy: lessons learned and future directions [Texte imprimé et/ou numérique] / C. A. ERICKSON, Auteur ; M. H. DAVENPORT, Auteur ; T. L. SCHAEFER, Auteur ; L. K. WINK, Auteur ; Ernest V. PEDAPATI, Auteur ; J. A. SWEENEY, Auteur ; S. E. FITZPATRICK, Auteur ; W. Ted BROWN, Auteur ; Dejan B. BUDIMIROVIC, Auteur ; Randi J. HAGERMAN, Auteur ; D. HESSL, Auteur ; W. E. KAUFMANN, Auteur ; Elizabeth BERRY-KRAVIS, Auteur . - p.7. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.7 Mots-clés : Drug development  Fragile X syndrome  Genetic disorder  Targeted treatments  Translational treatment Index. décimale : PER Périodiques Résumé : Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts. En ligne : http://dx.doi.org/10.1186/s11689-017-9186-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349

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