Characterization of early communicative behavior in mouse models of neurofibromatosis type 1 / Susan E. MALONEY in Autism Research, 11-1 (January 2018)  

Public ISBD [article]  inAutism Research > 11-1 (January 2018) . - p.44-58 Titre : Characterization of early communicative behavior in mouse models of neurofibromatosis type 1 Type de document : texte imprimé Auteurs : Susan E. MALONEY, Auteur ; Krystal C. CHANDLER, Auteur ; Corina ANASTASAKI, Auteur ; Michael A. RIEGER, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur Article en page(s) : p.44-58 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Neurofibromatosis type 1 (NF1) is a monogenic neurodevelopmental disease caused by germline loss‐of‐function mutations in the NF1 tumor suppressor gene. Cognitive impairments are observed in approximately 80% of children with this disease, with 45–60% exhibiting autism spectrum disorder (ASD) symptomatology. In light of the high comorbidity rate between ASD and NF1, we assessed early communicative behavior by maternal‐separation induced pup ultrasonic vocalizations (USV) and developmental milestones in two distinct Nf1 genetically engineered models, one modeling clinical germline heterozygous loss of Nf1 function (Nf1+/– mice), and a second with somatic biallelic Nf1 inactivation in neuroglial progenitor cells (Nf1GFAPCKO mice). We observed altered USV production in both models: Nf1+/– mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1GFAPCKO mice demonstrated a decrease in USVs. Developmental milestones, such as weight, pinnae detachment, and eye opening, were not disrupted in either model, indicating the USV deficits were not due to gross developmental delay, and likely reflected more specific alterations in USV circuitry. In this respect, increased whole‐brain serotonin was observed in Nf1+/– mice, but whole‐brain levels of dopamine and its metabolites were unchanged at the age of peak USV disruption, and USV alterations did not correlate with overall level of neurofibromin loss. The early communicative phenotypes reported herein should motivate further studies into the risks mediated by haploinsufficiency and biallelic deletion of Nf1 across a full battery of ASD‐relevant behavioral phenotypes, and a targeted analysis of underlying circuitry disruptions. Autism Res 2018, 11: 44–58. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder caused by mutation of the NF1 gene, in which 80% of affected children exhibit cognitive and behavioral issues. Based on emerging evidence that NF1 may be an autism predisposition gene, we examined autism spectrum disorder (ASD)‐relevant early communicative behavior in Nf1 mouse models and observed alterations in both models. The changes in early communicative behavior in Nf1 mutant mice should motivate further studies into the causative factors and potential treatments for ASD arising in the context of NF1. En ligne : https://doi.org/10.1002/aur.1853 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=333 [article] Characterization of early communicative behavior in mouse models of neurofibromatosis type 1 [texte imprimé] / Susan E. MALONEY, Auteur ; Krystal C. CHANDLER, Auteur ; Corina ANASTASAKI, Auteur ; Michael A. RIEGER, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur . - p.44-58. Langues : Anglais (eng) in Autism Research > 11-1 (January 2018) . - p.44-58 Index. décimale : PER Périodiques Résumé : Neurofibromatosis type 1 (NF1) is a monogenic neurodevelopmental disease caused by germline loss‐of‐function mutations in the NF1 tumor suppressor gene. Cognitive impairments are observed in approximately 80% of children with this disease, with 45–60% exhibiting autism spectrum disorder (ASD) symptomatology. In light of the high comorbidity rate between ASD and NF1, we assessed early communicative behavior by maternal‐separation induced pup ultrasonic vocalizations (USV) and developmental milestones in two distinct Nf1 genetically engineered models, one modeling clinical germline heterozygous loss of Nf1 function (Nf1+/– mice), and a second with somatic biallelic Nf1 inactivation in neuroglial progenitor cells (Nf1GFAPCKO mice). We observed altered USV production in both models: Nf1+/– mice exhibited both increased USVs across development and alterations in aspects of pitch, while Nf1GFAPCKO mice demonstrated a decrease in USVs. Developmental milestones, such as weight, pinnae detachment, and eye opening, were not disrupted in either model, indicating the USV deficits were not due to gross developmental delay, and likely reflected more specific alterations in USV circuitry. In this respect, increased whole‐brain serotonin was observed in Nf1+/– mice, but whole‐brain levels of dopamine and its metabolites were unchanged at the age of peak USV disruption, and USV alterations did not correlate with overall level of neurofibromin loss. The early communicative phenotypes reported herein should motivate further studies into the risks mediated by haploinsufficiency and biallelic deletion of Nf1 across a full battery of ASD‐relevant behavioral phenotypes, and a targeted analysis of underlying circuitry disruptions. Autism Res 2018, 11: 44–58. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder caused by mutation of the NF1 gene, in which 80% of affected children exhibit cognitive and behavioral issues. Based on emerging evidence that NF1 may be an autism predisposition gene, we examined autism spectrum disorder (ASD)‐relevant early communicative behavior in Nf1 mouse models and observed alterations in both models. The changes in early communicative behavior in Nf1 mutant mice should motivate further studies into the causative factors and potential treatments for ASD arising in the context of NF1. En ligne : https://doi.org/10.1002/aur.1853 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=333

Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders / Rachel M. RAHN in Journal of Neurodevelopmental Disorders, 13 (2021)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 13 (2021) Titre : Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders Type de document : texte imprimé Auteurs : Rachel M. RAHN, Auteur ; Claire T. WEICHSELBAUM, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur ; Susan E. MALONEY, Auteur Langues : Anglais (eng) Mots-clés : Animals  Disease Models, Animal  Gait  Humans  Mice  Neurodevelopmental Disorders/genetics  Neurofibromatosis Type 1  Williams Syndrome  neurodevelopmental disorders  precision medicine Index. décimale : PER Périodiques Résumé : BACKGROUND: Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. METHODS: We characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1(+/R681X) mouse, which models a NF1 patient-derived heterozygous germline NF1 mutation. Longitudinal data were collected across four developmental time points (postnatal days 21-30) and one early adulthood time point. RESULTS: Compared to wildtype littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across development in the Nf1(+/R681X) mice persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in the CD model largely resolved by adulthood. CONCLUSIONS: These findings suggest that the subcomponents of gait affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models and a platform to examining circuits or longitudinal therapeutics. En ligne : https://dx.doi.org/10.1186/s11689-021-09359-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders [texte imprimé] / Rachel M. RAHN, Auteur ; Claire T. WEICHSELBAUM, Auteur ; David H. GUTMANN, Auteur ; Joseph D. DOUGHERTY, Auteur ; Susan E. MALONEY, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 13 (2021) Mots-clés : Animals  Disease Models, Animal  Gait  Humans  Mice  Neurodevelopmental Disorders/genetics  Neurofibromatosis Type 1  Williams Syndrome  neurodevelopmental disorders  precision medicine Index. décimale : PER Périodiques Résumé : BACKGROUND: Motor deficits such as abnormal gait are an underappreciated yet characteristic phenotype of many neurodevelopmental disorders (NDDs), including Williams Syndrome (WS) and Neurofibromatosis Type 1 (NF1). Compared to cognitive phenotypes, gait phenotypes are readily and comparably assessed in both humans and model organisms and are controlled by well-defined CNS circuits. Discovery of a common gait phenotype between NDDs might suggest shared cellular and molecular deficits and highlight simple outcome variables to potentially quantify longitudinal treatment efficacy in NDDs. METHODS: We characterized gait using the DigiGait assay in two different murine NDD models: the complete deletion (CD) mouse, which models hemizygous loss of the complete WS locus, and the Nf1(+/R681X) mouse, which models a NF1 patient-derived heterozygous germline NF1 mutation. Longitudinal data were collected across four developmental time points (postnatal days 21-30) and one early adulthood time point. RESULTS: Compared to wildtype littermate controls, both models displayed markedly similar spatial, temporal, and postural gait abnormalities during development. Developing CD mice also displayed significant decreases in variability metrics. Multiple gait abnormalities observed across development in the Nf1(+/R681X) mice persisted into early adulthood, including increased stride length and decreased stride frequency, while developmental abnormalities in the CD model largely resolved by adulthood. CONCLUSIONS: These findings suggest that the subcomponents of gait affected in NDDs show overlap between disorders as well as some disorder-specific features, which may change over the course of development. Our incorporation of spatial, temporal, and postural gait measures also provides a template for gait characterization in other NDD models and a platform to examining circuits or longitudinal therapeutics. En ligne : https://dx.doi.org/10.1186/s11689-021-09359-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

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