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 et/ou numérique 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 et/ou numérique] / 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

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 et/ou numérique 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-1R? 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 et/ou numérique] / 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-1R? 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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