Bridging the Gap between Genes and Behavior: Brain-Derived Neurotrophic Factor and the mTOR Pathway in Idiopathic Autism / Margaret FAHNESTOCK in Autism - Open Access, 5-2 ([01/03/2015])  

Public ISBD [article]  inAutism - Open Access > 5-2 [01/03/2015] . - 10 p. Titre : Bridging the Gap between Genes and Behavior: Brain-Derived Neurotrophic Factor and the mTOR Pathway in Idiopathic Autism Type de document : texte imprimé Auteurs : Margaret FAHNESTOCK, Auteur ; Chiara NICOLINI, Auteur Article en page(s) : 10 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Although autism is highly genetic, “idiopathic” cases, for which there is no known genetic basis, may be due to epigenetic or environmental factors. Indeed, recent efforts have been highly successful in identifying hundreds of genes, as well as interacting epigenetic and environmental factors that contribute to autism susceptibility, corroborating the importance of gene x environment interactions in the etiology of autism. Nevertheless, a more thorough understanding of the proteins and pathways that lead from genes to behavior is desperately needed. Genetic studies have implicated molecules involved in synapse development and plasticity in autism pathogenesis. Among these are brain-derived neurotrophic factor (BDNF), its receptor, tropomyosin-related kinase B(TrkB), and their signaling pathways including mammalian target of rapamycin (mTOR), which is increased in most forms of syndromic autism. Notably, abnormalities in these molecules have also been found in idiopathic autism. Postmortem brain tissue of subjects with idiopathic autism exhibits imbalances in BDNF isoforms, reduced TrkB and downstream effectors PI3 kinase (PI3K), mTOR, Epidermal growth factor receptor pathway substrate 8 (Eps8) and the excitatory synaptic marker postsynaptic density protein 95 kDa (PSD-95). Furthermore, similar TrkB pathway deficits including reduced TrkB/mTOR signaling and PSD-95, along with autistic-like behavior, have been found in valproic acid-exposed rodents, a model of environmental/epigenetic causes of autism. Our studies in both human idiopathic autism and the valproic acid-induced rodent model suggest that decreased signaling through the mTOR pathway can be as damaging as its over-activation. En ligne : https://dx.doi.org/10.4172/2165-7890.1000143 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=409 [article] Bridging the Gap between Genes and Behavior: Brain-Derived Neurotrophic Factor and the mTOR Pathway in Idiopathic Autism [texte imprimé] / Margaret FAHNESTOCK, Auteur ; Chiara NICOLINI, Auteur . - 10 p. Langues : Anglais (eng) in Autism - Open Access > 5-2 [01/03/2015] . - 10 p. Index. décimale : PER Périodiques Résumé : Although autism is highly genetic, “idiopathic” cases, for which there is no known genetic basis, may be due to epigenetic or environmental factors. Indeed, recent efforts have been highly successful in identifying hundreds of genes, as well as interacting epigenetic and environmental factors that contribute to autism susceptibility, corroborating the importance of gene x environment interactions in the etiology of autism. Nevertheless, a more thorough understanding of the proteins and pathways that lead from genes to behavior is desperately needed. Genetic studies have implicated molecules involved in synapse development and plasticity in autism pathogenesis. Among these are brain-derived neurotrophic factor (BDNF), its receptor, tropomyosin-related kinase B(TrkB), and their signaling pathways including mammalian target of rapamycin (mTOR), which is increased in most forms of syndromic autism. Notably, abnormalities in these molecules have also been found in idiopathic autism. Postmortem brain tissue of subjects with idiopathic autism exhibits imbalances in BDNF isoforms, reduced TrkB and downstream effectors PI3 kinase (PI3K), mTOR, Epidermal growth factor receptor pathway substrate 8 (Eps8) and the excitatory synaptic marker postsynaptic density protein 95 kDa (PSD-95). Furthermore, similar TrkB pathway deficits including reduced TrkB/mTOR signaling and PSD-95, along with autistic-like behavior, have been found in valproic acid-exposed rodents, a model of environmental/epigenetic causes of autism. Our studies in both human idiopathic autism and the valproic acid-induced rodent model suggest that decreased signaling through the mTOR pathway can be as damaging as its over-activation. En ligne : https://dx.doi.org/10.4172/2165-7890.1000143 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=409

Clustering the autisms using glutamate synapse protein interaction networks from cortical and hippocampal tissue of seven mouse models / Emily A. BROWN in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 48p. Titre : Clustering the autisms using glutamate synapse protein interaction networks from cortical and hippocampal tissue of seven mouse models Type de document : texte imprimé Auteurs : Emily A. BROWN, Auteur ; Jonathan D. LAUTZ, Auteur ; Tessa R. DAVIS, Auteur ; Edward P. GNIFFKE, Auteur ; Alison A.W. VANSCHOIACK, Auteur ; Steven C. NEIER, Auteur ; Noah TASHBOOK, Auteur ; Chiara NICOLINI, Auteur ; Margaret FAHNESTOCK, Auteur ; Adam G. SCHRUM, Auteur ; Stephen E.P. SMITH, Auteur Article en page(s) : 48p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorders (ASDs) are a heterogeneous group of behaviorally defined disorders and are associated with hundreds of rare genetic mutations and several environmental risk factors. Mouse models of specific risk factors have been successful in identifying molecular mechanisms associated with a given factor. However, comparisons among different models to elucidate underlying common pathways or to define clusters of biologically relevant disease subtypes have been complicated by different methodological approaches or different brain regions examined by the labs that developed each model. Here, we use a novel proteomic technique, quantitative multiplex co-immunoprecipitation or QMI, to make a series of identical measurements of a synaptic protein interaction network in seven different animal models. We aim to identify molecular disruptions that are common to multiple models. Methods: QMI was performed on 92 hippocampal and cortical samples taken from seven mouse models of ASD: Shank3B, Shank3Deltaex4-9, Ube3a(2xTG), TSC2, FMR1, and CNTNAP2 mutants, as well as E12.5 VPA (maternal valproic acid injection on day 12.5 post-conception). The QMI panel targeted a network of 16 interacting, ASD-linked, synaptic proteins, probing 240 potential co-associations. A custom non-parametric statistical test was used to call significant differences between ASD models and littermate controls, and Hierarchical Clustering by Principal Components was used to cluster the models using mean log2 fold change values. Results: Each model displayed a unique set of disrupted interactions, but some interactions were disrupted in multiple models. These tended to be interactions that are known to change with synaptic activity. Clustering revealed potential relationships among models and suggested deficits in AKT signaling in Ube3a(2xTG) mice, which were confirmed by phospho-western blots. Conclusions: These data highlight the great heterogeneity among models, but suggest that high-dimensional measures of a synaptic protein network may allow differentiation of subtypes of ASD with shared molecular pathology. En ligne : https://dx.doi.org/10.1186/s13229-018-0229-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 [article] Clustering the autisms using glutamate synapse protein interaction networks from cortical and hippocampal tissue of seven mouse models [texte imprimé] / Emily A. BROWN, Auteur ; Jonathan D. LAUTZ, Auteur ; Tessa R. DAVIS, Auteur ; Edward P. GNIFFKE, Auteur ; Alison A.W. VANSCHOIACK, Auteur ; Steven C. NEIER, Auteur ; Noah TASHBOOK, Auteur ; Chiara NICOLINI, Auteur ; Margaret FAHNESTOCK, Auteur ; Adam G. SCHRUM, Auteur ; Stephen E.P. SMITH, Auteur . - 48p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 48p. Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorders (ASDs) are a heterogeneous group of behaviorally defined disorders and are associated with hundreds of rare genetic mutations and several environmental risk factors. Mouse models of specific risk factors have been successful in identifying molecular mechanisms associated with a given factor. However, comparisons among different models to elucidate underlying common pathways or to define clusters of biologically relevant disease subtypes have been complicated by different methodological approaches or different brain regions examined by the labs that developed each model. Here, we use a novel proteomic technique, quantitative multiplex co-immunoprecipitation or QMI, to make a series of identical measurements of a synaptic protein interaction network in seven different animal models. We aim to identify molecular disruptions that are common to multiple models. Methods: QMI was performed on 92 hippocampal and cortical samples taken from seven mouse models of ASD: Shank3B, Shank3Deltaex4-9, Ube3a(2xTG), TSC2, FMR1, and CNTNAP2 mutants, as well as E12.5 VPA (maternal valproic acid injection on day 12.5 post-conception). The QMI panel targeted a network of 16 interacting, ASD-linked, synaptic proteins, probing 240 potential co-associations. A custom non-parametric statistical test was used to call significant differences between ASD models and littermate controls, and Hierarchical Clustering by Principal Components was used to cluster the models using mean log2 fold change values. Results: Each model displayed a unique set of disrupted interactions, but some interactions were disrupted in multiple models. These tended to be interactions that are known to change with synaptic activity. Clustering revealed potential relationships among models and suggested deficits in AKT signaling in Ube3a(2xTG) mice, which were confirmed by phospho-western blots. Conclusions: These data highlight the great heterogeneity among models, but suggest that high-dimensional measures of a synaptic protein network may allow differentiation of subtypes of ASD with shared molecular pathology. En ligne : https://dx.doi.org/10.1186/s13229-018-0229-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371

Insulin-Like Growth Factor and Insulin-Like Growth Factor Receptor Expression in Human Idiopathic Autism Fusiform Gyrus Tissue / Milena CIOANA in Autism Research, 13-6 (June 2020)  

Public ISBD [article]  inAutism Research > 13-6 (June 2020) . - p.897-907 Titre : Insulin-Like Growth Factor and Insulin-Like Growth Factor Receptor Expression in Human Idiopathic Autism Fusiform Gyrus Tissue Type de document : texte imprimé Auteurs : Milena CIOANA, Auteur ; Bernadeta MICHALSKI, Auteur ; Margaret FAHNESTOCK, Auteur Article en page(s) : p.897-907 Langues : Anglais (eng) Mots-clés : Igf-1  IGF-1 receptor  autism  fusiform gyrus  gene expression Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is believed to stem from defects in the establishment and maintenance of functional neuronal networks due to synaptic/spine dysfunction. The potent effects of IGF-1 on synaptic function, maintenance, and plasticity make it a potential target for treating ASD. This polypeptide hormone has proven to have beneficial effects in treating related developmental disorders like Rett syndrome, and its efficacy in ASD is currently being investigated in a pilot study. IGF-1 binds to its receptor (IGF-1R) in neurons and activates mitogen-activated protein kinase and PI3K/Akt signaling to produce biological effects on spine function. The PI3K/Akt pathway is dysregulated in ASD, including idiopathic autism, and is thus believed to play a role in the disorder. Despite this, no study has explored the levels of IGF-1 in the fusiform gyrus of idiopathic autism patients, an area known to be hypoactivated in ASD, and no study has examined IGF-1R in any part of the brain. The present study explored whether IGF-1 or IGF-1R levels are altered in human idiopathic autism. RNA and protein were extracted from post-mortem human fusiform gyrus tissue of normal controls (n = 20) and subjects with idiopathic autism (n = 15). qRT-PCR for IGF-1 and IGF-1R were performed, along with total IGF-1 ELISA and IGF-1Rβ Western blots. The levels of both IGF-1 and IGF-1R mRNA and protein were equivalent between the two groups, suggesting that although IGF-1 may be useful for ASD treatment, IGF-1 and IGF-1R are not implicated in the pathogenesis of idiopathic autism. Autism Res 2020, 13: 897-907. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: IGF-1 is being tested for the treatment of autism and related disorders. Despite promising results, it is unknown if IGF-1 or its receptor are present in abnormal levels in patients with autism. This study showed that patients with autism have normal levels of IGF-1 and its receptor in the brain, suggesting that although IGF-1 is a promising treatment, disruption of IGF-1 levels or signaling through its receptor does not seem to be a cause of autism. En ligne : http://dx.doi.org/10.1002/aur.2291 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Insulin-Like Growth Factor and Insulin-Like Growth Factor Receptor Expression in Human Idiopathic Autism Fusiform Gyrus Tissue [texte imprimé] / Milena CIOANA, Auteur ; Bernadeta MICHALSKI, Auteur ; Margaret FAHNESTOCK, Auteur . - p.897-907. Langues : Anglais (eng) in Autism Research > 13-6 (June 2020) . - p.897-907 Mots-clés : Igf-1  IGF-1 receptor  autism  fusiform gyrus  gene expression Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is believed to stem from defects in the establishment and maintenance of functional neuronal networks due to synaptic/spine dysfunction. The potent effects of IGF-1 on synaptic function, maintenance, and plasticity make it a potential target for treating ASD. This polypeptide hormone has proven to have beneficial effects in treating related developmental disorders like Rett syndrome, and its efficacy in ASD is currently being investigated in a pilot study. IGF-1 binds to its receptor (IGF-1R) in neurons and activates mitogen-activated protein kinase and PI3K/Akt signaling to produce biological effects on spine function. The PI3K/Akt pathway is dysregulated in ASD, including idiopathic autism, and is thus believed to play a role in the disorder. Despite this, no study has explored the levels of IGF-1 in the fusiform gyrus of idiopathic autism patients, an area known to be hypoactivated in ASD, and no study has examined IGF-1R in any part of the brain. The present study explored whether IGF-1 or IGF-1R levels are altered in human idiopathic autism. RNA and protein were extracted from post-mortem human fusiform gyrus tissue of normal controls (n = 20) and subjects with idiopathic autism (n = 15). qRT-PCR for IGF-1 and IGF-1R were performed, along with total IGF-1 ELISA and IGF-1Rβ Western blots. The levels of both IGF-1 and IGF-1R mRNA and protein were equivalent between the two groups, suggesting that although IGF-1 may be useful for ASD treatment, IGF-1 and IGF-1R are not implicated in the pathogenesis of idiopathic autism. Autism Res 2020, 13: 897-907. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: IGF-1 is being tested for the treatment of autism and related disorders. Despite promising results, it is unknown if IGF-1 or its receptor are present in abnormal levels in patients with autism. This study showed that patients with autism have normal levels of IGF-1 and its receptor in the brain, suggesting that although IGF-1 is a promising treatment, disruption of IGF-1 levels or signaling through its receptor does not seem to be a cause of autism. En ligne : http://dx.doi.org/10.1002/aur.2291 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

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