MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders / Sarah 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 Auteurs : Sarah C. BORRIE, Auteur ; Ellen PLASSCHAERT, Auteur ; Zsuzsanna CALLAERTS-VEGH, Auteur ; Akihiko YOSHIMURA, Auteur ; Rudi D'HOOGE, Auteur ; Ype ELGERSMA, Auteur ; Steven A. KUSHNER, Auteur ; Eric LEGIUS, Auteur ; Hilde 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] / Sarah C. BORRIE, Auteur ; Ellen PLASSCHAERT, Auteur ; Zsuzsanna CALLAERTS-VEGH, Auteur ; Akihiko YOSHIMURA, Auteur ; Rudi D'HOOGE, Auteur ; Ype ELGERSMA, Auteur ; Steven A. KUSHNER, Auteur ; Eric LEGIUS, Auteur ; Hilde 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

Psychotic experiences and future school performance in childhood: a population-based cohort study / Lisa R STEENKAMP in Journal of Child Psychology and Psychiatry, 62-3 (March 2021)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 62-3 (March 2021) . - p.357-365 Titre : Psychotic experiences and future school performance in childhood: a population-based cohort study Type de document : texte imprimé Auteurs : Lisa R STEENKAMP, Auteur ; Koen BOLHUIS, Auteur ; Laura M.E. BLANKEN, Auteur ; Maartje P.C.M. LUIJK, Auteur ; Manon H.J. HILLEGERS, Auteur ; Steven A. KUSHNER, Auteur ; Henning TIEMEIER, Auteur Article en page(s) : p.357-365 Langues : Anglais (eng) Mots-clés : Psychosis  cognitive impairment  intelligence  school children  school performance Index. décimale : PER Périodiques Résumé : BACKGROUND: Psychotic experiences are common in childhood and an important risk indicator of adverse mental health outcomes. However, little is known about the association of psychotic experiences with functional outcomes in childhood, particularly regarding school performance. The aim of the present study was to examine whether psychotic experiences were prospectively related to school performance in childhood. METHODS: This study was embedded in the population-based Generation R Study (N = 2,362). Psychotic experiences were assessed using self-reports on hallucinations at age 10 years. School performance was assessed using a standardized national school performance test at age 12 years. We considered the total school performance score, as well as language and mathematics subscales. Analyses were adjusted for sociodemographic characteristics, maternal nonverbal IQ, nonverbal IQ at age 6 years and co-occurring psychopathology at age 10 years. RESULTS: Psychotic experiences were prospectively associated with poorer school performance scores (B = -0.61, 95% CI [-0.98;-0.25], p = .001), as well as poorer language (B(percentile rank score)  = -2.00, 95% CI [-3.20;-0.79], p = .001) and mathematical ability (B(percentile rank score)  = -1.75, 95% CI [-2.99;-0.51], p = .006). These associations remained after additional adjustment for nonverbal IQ at age 6 years (B = -0.51, 95% CI [-0.86;-0.16], p = .005), and co-occurring internalizing (B = -0.40, 95% CI [-0.77;-0.03], p = .036) and externalizing problems (B = -0.40, 95% CI [-0.75;-0.04], p = .029), but not attention problems (B = -0.10, 95% CI [-0.47;0.26], p = .57). CONCLUSIONS: Children with psychotic experiences had lower school performance scores than their nonaffected peers. The finding was independent of sociodemographic characteristics, intelligence and co-occurring internalizing and externalizing problems, but not attention problems. This study suggests that psychotic experiences are associated with childhood functional impairments, although the relatively small effects and the role of attention problems warrant further exploration. En ligne : http://dx.doi.org/10.1111/jcpp.13281 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=443 [article] Psychotic experiences and future school performance in childhood: a population-based cohort study [texte imprimé] / Lisa R STEENKAMP, Auteur ; Koen BOLHUIS, Auteur ; Laura M.E. BLANKEN, Auteur ; Maartje P.C.M. LUIJK, Auteur ; Manon H.J. HILLEGERS, Auteur ; Steven A. KUSHNER, Auteur ; Henning TIEMEIER, Auteur . - p.357-365. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 62-3 (March 2021) . - p.357-365 Mots-clés : Psychosis  cognitive impairment  intelligence  school children  school performance Index. décimale : PER Périodiques Résumé : BACKGROUND: Psychotic experiences are common in childhood and an important risk indicator of adverse mental health outcomes. However, little is known about the association of psychotic experiences with functional outcomes in childhood, particularly regarding school performance. The aim of the present study was to examine whether psychotic experiences were prospectively related to school performance in childhood. METHODS: This study was embedded in the population-based Generation R Study (N = 2,362). Psychotic experiences were assessed using self-reports on hallucinations at age 10 years. School performance was assessed using a standardized national school performance test at age 12 years. We considered the total school performance score, as well as language and mathematics subscales. Analyses were adjusted for sociodemographic characteristics, maternal nonverbal IQ, nonverbal IQ at age 6 years and co-occurring psychopathology at age 10 years. RESULTS: Psychotic experiences were prospectively associated with poorer school performance scores (B = -0.61, 95% CI [-0.98;-0.25], p = .001), as well as poorer language (B(percentile rank score)  = -2.00, 95% CI [-3.20;-0.79], p = .001) and mathematical ability (B(percentile rank score)  = -1.75, 95% CI [-2.99;-0.51], p = .006). These associations remained after additional adjustment for nonverbal IQ at age 6 years (B = -0.51, 95% CI [-0.86;-0.16], p = .005), and co-occurring internalizing (B = -0.40, 95% CI [-0.77;-0.03], p = .036) and externalizing problems (B = -0.40, 95% CI [-0.75;-0.04], p = .029), but not attention problems (B = -0.10, 95% CI [-0.47;0.26], p = .57). CONCLUSIONS: Children with psychotic experiences had lower school performance scores than their nonaffected peers. The finding was independent of sociodemographic characteristics, intelligence and co-occurring internalizing and externalizing problems, but not attention problems. This study suggests that psychotic experiences are associated with childhood functional impairments, although the relatively small effects and the role of attention problems warrant further exploration. En ligne : http://dx.doi.org/10.1111/jcpp.13281 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=443

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