T-Brain-1 – A Potential Master Regulator in Autism Spectrum Disorders / Hsiu-Chun CHUANG in Autism Research, 8-4 (August 2015)  

Public ISBD [article]  inAutism Research > 8-4 (August 2015) . - p.412-426 Titre : T-Brain-1 – A Potential Master Regulator in Autism Spectrum Disorders Type de document : Texte imprimé et/ou numérique Auteurs : Hsiu-Chun CHUANG, Auteur ; Tzyy-Nan HUANG, Auteur ; Yi-Ping HSUEH, Auteur Article en page(s) : p.412-426 Langues : Anglais (eng) Mots-clés : Baiap2  cell adhesion  Gad1  Kiaa0319  transcriptional regulation Index. décimale : PER Périodiques Résumé : T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor. It is therefore possible that TBR1 controls the expression of other autism risk factors. The downstream genes of TBR1 have been identified using microarray and promoter analyses. In this study, we annotated individual genes downstream of TBR1 and investigated any associations with ASDs through extensive literature searches. Of 124 TBR1 target genes, 23 were reported to be associated with ASDs. In addition, one gene, Kiaa0319, is a known causative gene for dyslexia, a disorder frequently associated with autism. A change in expression level in 10 of these 24 genes has been previously confirmed. We further validated the alteration of RNA expression levels of Kiaa0319, Baiap2, and Gad1 in Tbr1 deficient mice. Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis. A further five of the 24 genes (Cd44, Cdh8, Cntn6, Gpc6, and Ntng1) encode membrane proteins that regulate cell adhesion and axonal outgrowth. These genes likely contribute to the role of TBR1 in regulation of neuronal migration and axonal extension. Besides, decreases in Grin2b expression and increases in Gad1 expression imply that neuronal activity may be aberrant in Tbr1 deficient mice. These analyses provide direction for future experiments to reveal the pathogenic mechanism of autism. Autism Res 2015, 8: 412–426. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1456 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=268 [article] T-Brain-1 – A Potential Master Regulator in Autism Spectrum Disorders [Texte imprimé et/ou numérique] / Hsiu-Chun CHUANG, Auteur ; Tzyy-Nan HUANG, Auteur ; Yi-Ping HSUEH, Auteur . - p.412-426. Langues : Anglais (eng) in Autism Research > 8-4 (August 2015) . - p.412-426 Mots-clés : Baiap2  cell adhesion  Gad1  Kiaa0319  transcriptional regulation Index. décimale : PER Périodiques Résumé : T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor. It is therefore possible that TBR1 controls the expression of other autism risk factors. The downstream genes of TBR1 have been identified using microarray and promoter analyses. In this study, we annotated individual genes downstream of TBR1 and investigated any associations with ASDs through extensive literature searches. Of 124 TBR1 target genes, 23 were reported to be associated with ASDs. In addition, one gene, Kiaa0319, is a known causative gene for dyslexia, a disorder frequently associated with autism. A change in expression level in 10 of these 24 genes has been previously confirmed. We further validated the alteration of RNA expression levels of Kiaa0319, Baiap2, and Gad1 in Tbr1 deficient mice. Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis. A further five of the 24 genes (Cd44, Cdh8, Cntn6, Gpc6, and Ntng1) encode membrane proteins that regulate cell adhesion and axonal outgrowth. These genes likely contribute to the role of TBR1 in regulation of neuronal migration and axonal extension. Besides, decreases in Grin2b expression and increases in Gad1 expression imply that neuronal activity may be aberrant in Tbr1 deficient mice. These analyses provide direction for future experiments to reveal the pathogenic mechanism of autism. Autism Res 2015, 8: 412–426. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1456 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=268

Dietary zinc supplementation rescues fear-based learning and synaptic function in the Tbr1(+/-) mouse model of autism spectrum disorders / Kevin LEE in Molecular Autism, 13 (2022)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 13 p. Titre : Dietary zinc supplementation rescues fear-based learning and synaptic function in the Tbr1(+/-) mouse model of autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : Kevin LEE, Auteur ; Yewon JUNG, Auteur ; Yukti VYAS, Auteur ; Imogen SKELTON, Auteur ; Wickliffe C. ABRAHAM, Auteur ; Yi-Ping HSUEH, Auteur ; Johanna M. MONTGOMERY, Auteur Article en page(s) : 13 p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Dietary Supplements  Disease Models, Animal  Fear/physiology  Humans  Mice  Microfilament Proteins/metabolism  Nerve Tissue Proteins/genetics  Receptors, N-Methyl-D-Aspartate  Synapses/metabolism  T-Box Domain Proteins/metabolism/pharmacology  Zinc/metabolism/pharmacology  Amygdala  Autism spectrum disorder  Dietary zinc supplementation  Glutamatergic synapses  N-methyl-D-aspartate receptors  T-brain-1 Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by a dyad of behavioural symptoms-social and communication deficits and repetitive behaviours. Multiple aetiological genetic and environmental factors have been identified as causing or increasing the likelihood of ASD, including serum zinc deficiency. Our previous studies revealed that dietary zinc supplementation can normalise impaired social behaviours, excessive grooming, and heightened anxiety in a Shank3 mouse model of ASD, as well as the amelioration of synapse dysfunction. Here, we have examined the efficacy and breadth of dietary zinc supplementation as an effective therapeutic strategy utilising a non-Shank-related mouse model of ASD-mice with Tbr1 haploinsufficiency. METHODS: We performed behavioural assays, amygdalar slice whole-cell patch-clamp electrophysiology, and immunohistochemistry to characterise the synaptic mechanisms underlying the ASD-associated behavioural deficits observed in Tbr1(+/-) mice and the therapeutic potential of dietary zinc supplementation. Two-way analysis of variance (ANOVA) with ?ídák's post hoc test and one-way ANOVA with Tukey's post hoc multiple comparisons were performed for statistical analysis. RESULTS: Our data show that dietary zinc supplementation prevents impairments in auditory fear memory and social interaction, but not social novelty, in the Tbr1(+/-) mice. Tbr1 haploinsufficiency did not induce excessive grooming nor elevate anxiety in mice. At the synaptic level, dietary zinc supplementation reversed ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) hypofunction and normalised presynaptic function at thalamic-lateral amygdala (LA) synapses that are crucial for auditory fear memory. In addition, the zinc supplemented diet significantly restored the synaptic puncta density of the GluN1 subunit essential for functional NMDARs as well as SHANK3 expression in both the basal and lateral amygdala (BLA) of Tbr1(+/-) mice. LIMITATIONS: The therapeutic effect of dietary zinc supplementation observed in rodent models may not reproduce the same effects in human patients. The effect of dietary zinc supplementation on synaptic function in other brain structures affected by Tbr1 haploinsufficiency including olfactory bulb and anterior commissure will also need to be examined. CONCLUSIONS: Our data further the understanding of the molecular mechanisms underlying the effect of dietary zinc supplementation and verify the efficacy and breadth of its application as a potential treatment strategy for ASD. En ligne : http://dx.doi.org/10.1186/s13229-022-00494-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477 [article] Dietary zinc supplementation rescues fear-based learning and synaptic function in the Tbr1(+/-) mouse model of autism spectrum disorders [Texte imprimé et/ou numérique] / Kevin LEE, Auteur ; Yewon JUNG, Auteur ; Yukti VYAS, Auteur ; Imogen SKELTON, Auteur ; Wickliffe C. ABRAHAM, Auteur ; Yi-Ping HSUEH, Auteur ; Johanna M. MONTGOMERY, Auteur . - 13 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 13 p. Mots-clés : Animals  Autism Spectrum Disorder/genetics  Dietary Supplements  Disease Models, Animal  Fear/physiology  Humans  Mice  Microfilament Proteins/metabolism  Nerve Tissue Proteins/genetics  Receptors, N-Methyl-D-Aspartate  Synapses/metabolism  T-Box Domain Proteins/metabolism/pharmacology  Zinc/metabolism/pharmacology  Amygdala  Autism spectrum disorder  Dietary zinc supplementation  Glutamatergic synapses  N-methyl-D-aspartate receptors  T-brain-1 Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by a dyad of behavioural symptoms-social and communication deficits and repetitive behaviours. Multiple aetiological genetic and environmental factors have been identified as causing or increasing the likelihood of ASD, including serum zinc deficiency. Our previous studies revealed that dietary zinc supplementation can normalise impaired social behaviours, excessive grooming, and heightened anxiety in a Shank3 mouse model of ASD, as well as the amelioration of synapse dysfunction. Here, we have examined the efficacy and breadth of dietary zinc supplementation as an effective therapeutic strategy utilising a non-Shank-related mouse model of ASD-mice with Tbr1 haploinsufficiency. METHODS: We performed behavioural assays, amygdalar slice whole-cell patch-clamp electrophysiology, and immunohistochemistry to characterise the synaptic mechanisms underlying the ASD-associated behavioural deficits observed in Tbr1(+/-) mice and the therapeutic potential of dietary zinc supplementation. Two-way analysis of variance (ANOVA) with ?ídák's post hoc test and one-way ANOVA with Tukey's post hoc multiple comparisons were performed for statistical analysis. RESULTS: Our data show that dietary zinc supplementation prevents impairments in auditory fear memory and social interaction, but not social novelty, in the Tbr1(+/-) mice. Tbr1 haploinsufficiency did not induce excessive grooming nor elevate anxiety in mice. At the synaptic level, dietary zinc supplementation reversed ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) hypofunction and normalised presynaptic function at thalamic-lateral amygdala (LA) synapses that are crucial for auditory fear memory. In addition, the zinc supplemented diet significantly restored the synaptic puncta density of the GluN1 subunit essential for functional NMDARs as well as SHANK3 expression in both the basal and lateral amygdala (BLA) of Tbr1(+/-) mice. LIMITATIONS: The therapeutic effect of dietary zinc supplementation observed in rodent models may not reproduce the same effects in human patients. The effect of dietary zinc supplementation on synaptic function in other brain structures affected by Tbr1 haploinsufficiency including olfactory bulb and anterior commissure will also need to be examined. CONCLUSIONS: Our data further the understanding of the molecular mechanisms underlying the effect of dietary zinc supplementation and verify the efficacy and breadth of its application as a potential treatment strategy for ASD. En ligne : http://dx.doi.org/10.1186/s13229-022-00494-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477

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