Autism Spectrum Disorder in an Unselected Cohort of Children with Neurofibromatosis Type 1 (NF1) / S. EIJK in Journal of Autism and Developmental Disorders, 48-7 (July 2018)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 48-7 (July 2018) . - p.2278-2285 Titre : Autism Spectrum Disorder in an Unselected Cohort of Children with Neurofibromatosis Type 1 (NF1) Type de document : Texte imprimé et/ou numérique Auteurs : S. EIJK, Auteur ; S. E. MOUS, Auteur ; G. C. DIELEMAN, Auteur ; Bram DIERCKX, Auteur ; A. B. RIETMAN, Auteur ; P. F. A. DE NIJS, Auteur ; L. W. TEN HOOPEN, Auteur ; R. VAN MINKELEN, Auteur ; Y. ELGERSMA, Auteur ; Coriene E. CATSMAN-BERREVOETS, Auteur ; R. OOSTENBRINK, Auteur ; J. S. LEGERSTEE, Auteur Article en page(s) : p.2278-2285 Langues : Anglais (eng) Mots-clés : Autism diagnostic observation schedule  Autism spectrum disorder  Autistic traits  Neurofibromatosis type 1  Prevalence  Social responsiveness scale Index. décimale : PER Périodiques Résumé : In a non-selected sample of children with Neurofibromatosis type 1 (NF1) the prevalence rate of autism spectrum disorder (ASD) and predictive value of an observational (ADOS)-and questionnaire-based screening instrument were assessed. Complete data was available for 128 children. The prevalence rate for clinical ASD was 10.9%, which is clearly higher than in the general population. This prevalence rate is presumably more accurate than in previous studies that examined children with NF1 with an ASD presumption or solely based on screening instruments. The combined observational- and screening based classifications demonstrated the highest positive predictive value for DSM-IV diagnosis, highlighting the importance of using both instruments in children with NF1. En ligne : http://dx.doi.org/10.1007/s10803-018-3478-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=367 [article] Autism Spectrum Disorder in an Unselected Cohort of Children with Neurofibromatosis Type 1 (NF1) [Texte imprimé et/ou numérique] / S. EIJK, Auteur ; S. E. MOUS, Auteur ; G. C. DIELEMAN, Auteur ; Bram DIERCKX, Auteur ; A. B. RIETMAN, Auteur ; P. F. A. DE NIJS, Auteur ; L. W. TEN HOOPEN, Auteur ; R. VAN MINKELEN, Auteur ; Y. ELGERSMA, Auteur ; Coriene E. CATSMAN-BERREVOETS, Auteur ; R. OOSTENBRINK, Auteur ; J. S. LEGERSTEE, Auteur . - p.2278-2285. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 48-7 (July 2018) . - p.2278-2285 Mots-clés : Autism diagnostic observation schedule  Autism spectrum disorder  Autistic traits  Neurofibromatosis type 1  Prevalence  Social responsiveness scale Index. décimale : PER Périodiques Résumé : In a non-selected sample of children with Neurofibromatosis type 1 (NF1) the prevalence rate of autism spectrum disorder (ASD) and predictive value of an observational (ADOS)-and questionnaire-based screening instrument were assessed. Complete data was available for 128 children. The prevalence rate for clinical ASD was 10.9%, which is clearly higher than in the general population. This prevalence rate is presumably more accurate than in previous studies that examined children with NF1 with an ASD presumption or solely based on screening instruments. The combined observational- and screening based classifications demonstrated the highest positive predictive value for DSM-IV diagnosis, highlighting the importance of using both instruments in children with NF1. En ligne : http://dx.doi.org/10.1007/s10803-018-3478-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=367

A behavioral test battery for mouse models of Angelman syndrome: a powerful tool for testing drugs and novel Ube3a mutants / M. SONZOGNI in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 47p. Titre : A behavioral test battery for mouse models of Angelman syndrome: a powerful tool for testing drugs and novel Ube3a mutants Type de document : Texte imprimé et/ou numérique Auteurs : M. SONZOGNI, Auteur ; I. WALLAARD, Auteur ; S. S. SANTOS, Auteur ; J. KINGMA, Auteur ; D. DU MEE, Auteur ; G. M. VAN WOERDEN, Auteur ; Y. ELGERSMA, Auteur Article en page(s) : 47p. Langues : Anglais (eng) Mots-clés : Angelman syndrome  Mouse model, behavior, drug screening  UBE3A Index. décimale : PER Périodiques Résumé : Background: Angelman syndrome (AS) is a neurodevelopmental disorder caused by mutations affecting UBE3A function. AS is characterized by intellectual disability, impaired motor coordination, epilepsy, and behavioral abnormalities including autism spectrum disorder features. The development of treatments for AS heavily relies on the ability to test the efficacy of drugs in mouse models that show reliable, and preferably clinically relevant, phenotypes. We previously described a number of behavioral paradigms that assess phenotypes in the domains of motor performance, repetitive behavior, anxiety, and seizure susceptibility. Here, we set out to evaluate the robustness of these phenotypes when tested in a standardized test battery. We then used this behavioral test battery to assess the efficacy of minocycline and levodopa, which were recently tested in clinical trials of AS. Methods: We combined data of eight independent experiments involving 111 Ube3a mice and 120 wild-type littermate control mice. Using a meta-analysis, we determined the statistical power of the subtests and the effect of putative confounding factors, such as the effect of sex and of animal weight on rotarod performance. We further assessed the robustness of these phenotypes by comparing Ube3a mutants in different genetic backgrounds and by comparing the behavioral phenotypes of independently derived Ube3a-mutant lines. In addition, we investigated if the test battery allowed re-testing the same animals, which would allow a within-subject testing design. Results: We find that the test battery is robust across different Ube3a-mutant lines, but confirm and extend earlier studies that several phenotypes are very sensitive to genetic background. We further found that the audiogenic seizure susceptibility phenotype is fully reversible upon pharmacological treatment and highly suitable for dose-finding studies. In agreement with the clinical trial results, we found that minocycline and levodopa treatment of Ube3a mice did not show any sign of improved performance in our test battery. Conclusions: Our study provides a useful tool for preclinical drug testing to identify treatments for Angelman syndrome. Since the phenotypes are observed in several independently derived Ube3a lines, the test battery can also be employed to investigate the effect of specific Ube3a mutations on these phenotypes. En ligne : https://dx.doi.org/10.1186/s13229-018-0231-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] A behavioral test battery for mouse models of Angelman syndrome: a powerful tool for testing drugs and novel Ube3a mutants [Texte imprimé et/ou numérique] / M. SONZOGNI, Auteur ; I. WALLAARD, Auteur ; S. S. SANTOS, Auteur ; J. KINGMA, Auteur ; D. DU MEE, Auteur ; G. M. VAN WOERDEN, Auteur ; Y. ELGERSMA, Auteur . - 47p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 47p. Mots-clés : Angelman syndrome  Mouse model, behavior, drug screening  UBE3A Index. décimale : PER Périodiques Résumé : Background: Angelman syndrome (AS) is a neurodevelopmental disorder caused by mutations affecting UBE3A function. AS is characterized by intellectual disability, impaired motor coordination, epilepsy, and behavioral abnormalities including autism spectrum disorder features. The development of treatments for AS heavily relies on the ability to test the efficacy of drugs in mouse models that show reliable, and preferably clinically relevant, phenotypes. We previously described a number of behavioral paradigms that assess phenotypes in the domains of motor performance, repetitive behavior, anxiety, and seizure susceptibility. Here, we set out to evaluate the robustness of these phenotypes when tested in a standardized test battery. We then used this behavioral test battery to assess the efficacy of minocycline and levodopa, which were recently tested in clinical trials of AS. Methods: We combined data of eight independent experiments involving 111 Ube3a mice and 120 wild-type littermate control mice. Using a meta-analysis, we determined the statistical power of the subtests and the effect of putative confounding factors, such as the effect of sex and of animal weight on rotarod performance. We further assessed the robustness of these phenotypes by comparing Ube3a mutants in different genetic backgrounds and by comparing the behavioral phenotypes of independently derived Ube3a-mutant lines. In addition, we investigated if the test battery allowed re-testing the same animals, which would allow a within-subject testing design. Results: We find that the test battery is robust across different Ube3a-mutant lines, but confirm and extend earlier studies that several phenotypes are very sensitive to genetic background. We further found that the audiogenic seizure susceptibility phenotype is fully reversible upon pharmacological treatment and highly suitable for dose-finding studies. In agreement with the clinical trial results, we found that minocycline and levodopa treatment of Ube3a mice did not show any sign of improved performance in our test battery. Conclusions: Our study provides a useful tool for preclinical drug testing to identify treatments for Angelman syndrome. Since the phenotypes are observed in several independently derived Ube3a lines, the test battery can also be employed to investigate the effect of specific Ube3a mutations on these phenotypes. En ligne : https://dx.doi.org/10.1186/s13229-018-0231-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

A brain proteomic investigation of rapamycin effects in the Tsc1(+/-) mouse model / H. WESSELING in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 41p. Titre : A brain proteomic investigation of rapamycin effects in the Tsc1(+/-) mouse model Type de document : Texte imprimé et/ou numérique Auteurs : H. WESSELING, Auteur ; Y. ELGERSMA, Auteur ; S. BAHN, Auteur Article en page(s) : 41p. Langues : Anglais (eng) Mots-clés : Animal model  Proteomics  Rapamycin  Srm  Tuberous sclerosis Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a rare monogenic disorder characterized by benign tumors in multiple organs as well as a high prevalence of epilepsy, intellectual disability and autism. TSC is caused by inactivating mutations in the TSC1 or TSC2 genes. Heterozygocity induces hyperactivation of mTOR which can be inhibited by mTOR inhibitors, such as rapamycin, which have proven efficacy in the treatment of TSC-associated symptoms. The aim of the present study was (1) to identify molecular changes associated with social and cognitive deficits in the brain tissue of Tsc1(+/-) mice and (2) to investigate the molecular effects of rapamycin treatment, which has been shown to ameliorate genotype-related behavioural deficits. METHODS: Molecular alterations in the frontal cortex and hippocampus of Tsc1(+/-) and control mice, with or without rapamycin treatment, were investigated. A quantitative mass spectrometry-based shotgun proteomic approach (LC-MS(E)) was employed as an unbiased method to detect changes in protein levels. Changes identified in the initial profiling stage were validated using selected reaction monitoring (SRM). Protein Set Enrichment Analysis was employed to identify dysregulated pathways. RESULTS: LC-MS(E) analysis of Tsc1(+/-) mice and controls (n = 30) identified 51 proteins changed in frontal cortex and 108 in the hippocampus. Bioinformatic analysis combined with targeted proteomic validation revealed several dysregulated molecular pathways. Using targeted assays, proteomic alterations in the hippocampus validated the pathways "myelination", "dendrite," and "oxidative stress", an upregulation of ribosomal proteins and the mTOR kinase. LC-MS(E) analysis was also employed on Tsc1(+/-) and wildtype mice (n = 34) treated with rapamycin or vehicle. Rapamycin treatment exerted a stronger proteomic effect in Tsc1(+/-) mice with significant changes (mainly decreased expression) in 231 and 106 proteins, respectively. The cellular pathways "oxidative stress" and "apoptosis" were found to be affected in Tsc1(+/-) mice and the cellular compartments "myelin sheet" and "neurofilaments" were affected by rapamycin treatment. Thirty-three proteins which were altered in Tsc1(+/-) mice were normalized following rapamycin treatment, amongst them oxidative stress related proteins, myelin-specific and ribosomal proteins. CONCLUSIONS: Molecular changes in the Tsc1(+/-) mouse brain were more prominent in the hippocampus compared to the frontal cortex. Pathways linked to myelination and oxidative stress response were prominently affected and, at least in part, normalized following rapamycin treatment. The results could aid in the identification of novel drug targets for the treatment of cognitive, social and psychiatric symptoms in autism spectrum disorders. Similar pathways have also been implicated in other psychiatric and neurodegenerative disorders and could imply similar disease processes. Thus, the potential efficacy of mTOR inhibitors warrants further investigation not only for autism spectrum disorders but also for other neuropsychiatric and neurodegenerative diseases. En ligne : http://dx.doi.org/10.1186/s13229-017-0151-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] A brain proteomic investigation of rapamycin effects in the Tsc1(+/-) mouse model [Texte imprimé et/ou numérique] / H. WESSELING, Auteur ; Y. ELGERSMA, Auteur ; S. BAHN, Auteur . - 41p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 41p. Mots-clés : Animal model  Proteomics  Rapamycin  Srm  Tuberous sclerosis Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a rare monogenic disorder characterized by benign tumors in multiple organs as well as a high prevalence of epilepsy, intellectual disability and autism. TSC is caused by inactivating mutations in the TSC1 or TSC2 genes. Heterozygocity induces hyperactivation of mTOR which can be inhibited by mTOR inhibitors, such as rapamycin, which have proven efficacy in the treatment of TSC-associated symptoms. The aim of the present study was (1) to identify molecular changes associated with social and cognitive deficits in the brain tissue of Tsc1(+/-) mice and (2) to investigate the molecular effects of rapamycin treatment, which has been shown to ameliorate genotype-related behavioural deficits. METHODS: Molecular alterations in the frontal cortex and hippocampus of Tsc1(+/-) and control mice, with or without rapamycin treatment, were investigated. A quantitative mass spectrometry-based shotgun proteomic approach (LC-MS(E)) was employed as an unbiased method to detect changes in protein levels. Changes identified in the initial profiling stage were validated using selected reaction monitoring (SRM). Protein Set Enrichment Analysis was employed to identify dysregulated pathways. RESULTS: LC-MS(E) analysis of Tsc1(+/-) mice and controls (n = 30) identified 51 proteins changed in frontal cortex and 108 in the hippocampus. Bioinformatic analysis combined with targeted proteomic validation revealed several dysregulated molecular pathways. Using targeted assays, proteomic alterations in the hippocampus validated the pathways "myelination", "dendrite," and "oxidative stress", an upregulation of ribosomal proteins and the mTOR kinase. LC-MS(E) analysis was also employed on Tsc1(+/-) and wildtype mice (n = 34) treated with rapamycin or vehicle. Rapamycin treatment exerted a stronger proteomic effect in Tsc1(+/-) mice with significant changes (mainly decreased expression) in 231 and 106 proteins, respectively. The cellular pathways "oxidative stress" and "apoptosis" were found to be affected in Tsc1(+/-) mice and the cellular compartments "myelin sheet" and "neurofilaments" were affected by rapamycin treatment. Thirty-three proteins which were altered in Tsc1(+/-) mice were normalized following rapamycin treatment, amongst them oxidative stress related proteins, myelin-specific and ribosomal proteins. CONCLUSIONS: Molecular changes in the Tsc1(+/-) mouse brain were more prominent in the hippocampus compared to the frontal cortex. Pathways linked to myelination and oxidative stress response were prominently affected and, at least in part, normalized following rapamycin treatment. The results could aid in the identification of novel drug targets for the treatment of cognitive, social and psychiatric symptoms in autism spectrum disorders. Similar pathways have also been implicated in other psychiatric and neurodegenerative disorders and could imply similar disease processes. Thus, the potential efficacy of mTOR inhibitors warrants further investigation not only for autism spectrum disorders but also for other neuropsychiatric and neurodegenerative diseases. En ligne : http://dx.doi.org/10.1186/s13229-017-0151-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Delayed loss of UBE3A reduces the expression of Angelman syndrome-associated phenotypes / M. SONZOGNI in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 23p. Titre : Delayed loss of UBE3A reduces the expression of Angelman syndrome-associated phenotypes Type de document : Texte imprimé et/ou numérique Auteurs : M. SONZOGNI, Auteur ; J. HAKONEN, Auteur ; M. BERNABE KLEIJN, Auteur ; S. SILVA-SANTOS, Auteur ; M. C. JUDSON, Auteur ; B. D. PHILPOT, Auteur ; G. M. VAN WOERDEN, Auteur ; Y. ELGERSMA, Auteur Article en page(s) : 23p. Langues : Anglais (eng) Mots-clés : Angelman syndrome  Autism spectrum disorder  Mouse model  Phenotype  Seizure  Ube3a Index. décimale : PER Périodiques Résumé : Background: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutations affecting UBE3A gene expression. Previous studies in mice revealed distinct critical periods during neurodevelopment in which reactivation of Ube3a gene expression can prevent the onset of behavioral deficits. Whether UBE3A is required for brain function throughout life is unknown. Here, we address the importance of maintaining UBE3A expression after normal brain development. Findings: Using a conditional mouse, we deleted the Ube3a gene at three ages spanning brain maturation. We assessed the consequences of Ube3a gene deletion by testing the mice in behavioral tasks previously shown to produce robust phenotypes in AS model mice. Early embryonic deletion of Ube3a recapitulated all behavioral deficits of AS mice. In contrast, Ube3a gene deletion at 3 or 12 weeks of age did not have a significant effect on most behavioral tasks and did not increase seizure sensitivity. Conclusions: Taken together, these results emphasize that UBE3A critically impacts early brain development, but plays a more limited role in adulthood. Our findings provide important considerations for upcoming clinical trials in which UBE3A gene expression is reactivated and suggest that even transient UBE3A reinstatement during a critical window of early development is likely to prevent most adverse Angelman syndrome phenotypes. However, sustained UBE3A expression into adulthood is probably needed for optimal clinical benefit. En ligne : http://dx.doi.org/10.1186/s13229-019-0277-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=402 [article] Delayed loss of UBE3A reduces the expression of Angelman syndrome-associated phenotypes [Texte imprimé et/ou numérique] / M. SONZOGNI, Auteur ; J. HAKONEN, Auteur ; M. BERNABE KLEIJN, Auteur ; S. SILVA-SANTOS, Auteur ; M. C. JUDSON, Auteur ; B. D. PHILPOT, Auteur ; G. M. VAN WOERDEN, Auteur ; Y. ELGERSMA, Auteur . - 23p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 23p. Mots-clés : Angelman syndrome  Autism spectrum disorder  Mouse model  Phenotype  Seizure  Ube3a Index. décimale : PER Périodiques Résumé : Background: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutations affecting UBE3A gene expression. Previous studies in mice revealed distinct critical periods during neurodevelopment in which reactivation of Ube3a gene expression can prevent the onset of behavioral deficits. Whether UBE3A is required for brain function throughout life is unknown. Here, we address the importance of maintaining UBE3A expression after normal brain development. Findings: Using a conditional mouse, we deleted the Ube3a gene at three ages spanning brain maturation. We assessed the consequences of Ube3a gene deletion by testing the mice in behavioral tasks previously shown to produce robust phenotypes in AS model mice. Early embryonic deletion of Ube3a recapitulated all behavioral deficits of AS mice. In contrast, Ube3a gene deletion at 3 or 12 weeks of age did not have a significant effect on most behavioral tasks and did not increase seizure sensitivity. Conclusions: Taken together, these results emphasize that UBE3A critically impacts early brain development, but plays a more limited role in adulthood. Our findings provide important considerations for upcoming clinical trials in which UBE3A gene expression is reactivated and suggest that even transient UBE3A reinstatement during a critical window of early development is likely to prevent most adverse Angelman syndrome phenotypes. However, sustained UBE3A expression into adulthood is probably needed for optimal clinical benefit. En ligne : http://dx.doi.org/10.1186/s13229-019-0277-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=402

MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders / S. C. BORRIE in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 53 p. Titre : MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders Type de document : Texte imprimé et/ou numérique Auteurs : S. C. BORRIE, Auteur ; E. PLASSCHAERT, Auteur ; Z. CALLAERTS-VEGH, Auteur ; A. YOSHIMURA, Auteur ; R. D'HOOGE, Auteur ; Y. ELGERSMA, Auteur ; S. A. KUSHNER, Auteur ; E. LEGIUS, Auteur ; H. BREMS, Auteur Article en page(s) : 53 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Neurofibromatosis type 1  RASopathy  Social dominance  Spred1  Ultrasonic vocalization  declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: RASopathies are a group of disorders that result from mutations in genes coding for proteins involved in regulating the Ras-MAPK signaling pathway, and have an increased incidence of autism spectrum disorder (ASD). Legius syndrome is a rare RASopathy caused by loss-of-function mutations in the SPRED1 gene. The patient phenotype is similar to, but milder than, Neurofibromatosis type 1-another RASopathy caused by loss-of-function mutations in the NF1 gene. RASopathies exhibit increased activation of Ras-MAPK signaling and commonly manifest with cognitive impairments and ASD. Here, we investigated if a Spred1-/- mouse model for Legius syndrome recapitulates ASD-like symptoms, and whether targeting the Ras-MAPK pathway has therapeutic potential in this RASopathy mouse model. METHODS: We investigated social and communicative behaviors in Spred1-/- mice and probed therapeutic mechanisms underlying the observed behavioral phenotypes by pharmacological targeting of the Ras-MAPK pathway with the MEK inhibitor PD325901. RESULTS: Spred1-/- mice have robust increases in social dominance in the automated tube test and reduced adult ultrasonic vocalizations during social communication. Neonatal ultrasonic vocalization was also altered, with significant differences in spectral properties. Spred1-/- mice also exhibit impaired nesting behavior. Acute MEK inhibitor treatment in adulthood with PD325901 reversed the enhanced social dominance in Spred1-/- mice to normal levels, and improved nesting behavior in adult Spred1-/- mice. LIMITATIONS: This study used an acute treatment protocol to administer the drug. It is not known what the effects of longer-term treatment would be on behavior. Further studies titrating the lowest dose of this drug that is required to alter Spred1-/- social behavior are still required. Finally, our findings are in a homozygous mouse model, whereas patients carry heterozygous mutations. These factors should be considered before any translational conclusions are drawn. CONCLUSIONS: These results demonstrate for the first time that social behavior phenotypes in a mouse model for RASopathies (Spred1-/-) can be acutely reversed. This highlights a key role for Ras-MAPK dysregulation in mediating social behavior phenotypes in mouse models for ASD, suggesting that proper regulation of Ras-MAPK signaling is important for social behavior. En ligne : http://dx.doi.org/10.1186/s13229-021-00458-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders [Texte imprimé et/ou numérique] / S. C. BORRIE, Auteur ; E. PLASSCHAERT, Auteur ; Z. CALLAERTS-VEGH, Auteur ; A. YOSHIMURA, Auteur ; R. D'HOOGE, Auteur ; Y. ELGERSMA, Auteur ; S. A. KUSHNER, Auteur ; E. LEGIUS, Auteur ; H. BREMS, Auteur . - 53 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 53 p. Mots-clés : Autism spectrum disorder  Neurofibromatosis type 1  RASopathy  Social dominance  Spred1  Ultrasonic vocalization  declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: RASopathies are a group of disorders that result from mutations in genes coding for proteins involved in regulating the Ras-MAPK signaling pathway, and have an increased incidence of autism spectrum disorder (ASD). Legius syndrome is a rare RASopathy caused by loss-of-function mutations in the SPRED1 gene. The patient phenotype is similar to, but milder than, Neurofibromatosis type 1-another RASopathy caused by loss-of-function mutations in the NF1 gene. RASopathies exhibit increased activation of Ras-MAPK signaling and commonly manifest with cognitive impairments and ASD. Here, we investigated if a Spred1-/- mouse model for Legius syndrome recapitulates ASD-like symptoms, and whether targeting the Ras-MAPK pathway has therapeutic potential in this RASopathy mouse model. METHODS: We investigated social and communicative behaviors in Spred1-/- mice and probed therapeutic mechanisms underlying the observed behavioral phenotypes by pharmacological targeting of the Ras-MAPK pathway with the MEK inhibitor PD325901. RESULTS: Spred1-/- mice have robust increases in social dominance in the automated tube test and reduced adult ultrasonic vocalizations during social communication. Neonatal ultrasonic vocalization was also altered, with significant differences in spectral properties. Spred1-/- mice also exhibit impaired nesting behavior. Acute MEK inhibitor treatment in adulthood with PD325901 reversed the enhanced social dominance in Spred1-/- mice to normal levels, and improved nesting behavior in adult Spred1-/- mice. LIMITATIONS: This study used an acute treatment protocol to administer the drug. It is not known what the effects of longer-term treatment would be on behavior. Further studies titrating the lowest dose of this drug that is required to alter Spred1-/- social behavior are still required. Finally, our findings are in a homozygous mouse model, whereas patients carry heterozygous mutations. These factors should be considered before any translational conclusions are drawn. CONCLUSIONS: These results demonstrate for the first time that social behavior phenotypes in a mouse model for RASopathies (Spred1-/-) can be acutely reversed. This highlights a key role for Ras-MAPK dysregulation in mediating social behavior phenotypes in mouse models for ASD, suggesting that proper regulation of Ras-MAPK signaling is important for social behavior. En ligne : http://dx.doi.org/10.1186/s13229-021-00458-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

The role of ubiquitin ligase E3A in polarized contact guidance and rescue strategies in UBE3A-deficient hippocampal neurons / I. TONAZZINI in Molecular Autism, 10 (2019)  

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