Haploinsufficiency of autism causative gene Tbr1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice / T. N. HUANG in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 5 p. Titre : Haploinsufficiency of autism causative gene Tbr1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice Type de document : Texte imprimé et/ou numérique Auteurs : T. N. HUANG, Auteur ; T. L. YEN, Auteur ; L. R. QIU, Auteur ; H. C. CHUANG, Auteur ; J. P. LERCH, Auteur ; Y. P. HSUEH, Auteur Article en page(s) : 5 p. Langues : Anglais (eng) Mots-clés : *Autism spectrum disorders  *c-fos  *D-cycloserine  *Neuronal activation  *Olfactory bulb  *Olfactory discrimination  *T-brain-1  interests.Springer Nature remains neutral with regard to jurisdictional claims in  published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by Tbr1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in Tbr1 mutant mice. Methods: We used Tbr1 (+/-) mice as a model to investigate the function of TBR1 in olfactory sensation and discrimination of non-social odors. We employed a behavioral assay to characterize the olfactory defects of Tbr1 (+/-) mice. Magnetic resonance imaging (MRI) and histological analysis were applied to characterize anatomical features. Immunostaining was performed to further analyze differences in expression of TBR1 subfamily members (namely TBR1, TBR2, and TBX21), interneuron populations, and dendritic abnormalities in olfactory bulbs. Finally, C-FOS staining was used to monitor neuronal activation of the olfactory system upon odor stimulation. Results: Tbr1 (+/-) mice exhibited smaller olfactory bulbs and anterior commissures, reduced interneuron populations, and an abnormal dendritic morphology of mitral cells in the olfactory bulbs. Tbr1 haploinsufficiency specifically impaired olfactory discrimination but not olfactory sensation. Neuronal activation upon odorant stimulation was reduced in the glomerular layer of Tbr1 (+/-) olfactory bulbs. Furthermore, although the sizes of piriform and perirhinal cortices were not affected by Tbr1 deficiency, neuronal activation was reduced in these two cortical regions in response to odorant stimulation. These results suggest an impairment of neuronal activation in olfactory bulbs and defective connectivity from olfactory bulbs to the upper olfactory system in Tbr1 (+/-) mice. Systemic administration of D-cycloserine, an NMDAR co-agonist, ameliorated olfactory discrimination in Tbr1 (+/-) mice, suggesting that increased neuronal activity has a beneficial effect on Tbr1 deficiency. Conclusions: Tbr1 regulates neural circuits and activity in the olfactory system to control olfaction. Tbr1 (+/-) mice can serve as a suitable model for revealing how an autism causative gene controls neuronal circuits, neural activity, and autism-related behaviors. En ligne : https://dx.doi.org/10.1186/s13229-019-0257-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Haploinsufficiency of autism causative gene Tbr1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice [Texte imprimé et/ou numérique] / T. N. HUANG, Auteur ; T. L. YEN, Auteur ; L. R. QIU, Auteur ; H. C. CHUANG, Auteur ; J. P. LERCH, Auteur ; Y. P. HSUEH, Auteur . - 5 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 5 p. Mots-clés : *Autism spectrum disorders  *c-fos  *D-cycloserine  *Neuronal activation  *Olfactory bulb  *Olfactory discrimination  *T-brain-1  interests.Springer Nature remains neutral with regard to jurisdictional claims in  published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorders (ASD) exhibit two clusters of core symptoms, i.e., social and communication impairment, and repetitive behaviors and sensory abnormalities. Our previous study demonstrated that TBR1, a causative gene of ASD, controls axonal projection and neuronal activation of amygdala and regulates social interaction and vocal communication in a mouse model. Behavioral defects caused by Tbr1 haploinsufficiency can be ameliorated by increasing neural activity via D-cycloserine treatment, an N-methyl-D-aspartate receptor (NMDAR) coagonist. In this report, we investigate the role of TBR1 in regulating olfaction and test whether D-cycloserine can also improve olfactory defects in Tbr1 mutant mice. Methods: We used Tbr1 (+/-) mice as a model to investigate the function of TBR1 in olfactory sensation and discrimination of non-social odors. We employed a behavioral assay to characterize the olfactory defects of Tbr1 (+/-) mice. Magnetic resonance imaging (MRI) and histological analysis were applied to characterize anatomical features. Immunostaining was performed to further analyze differences in expression of TBR1 subfamily members (namely TBR1, TBR2, and TBX21), interneuron populations, and dendritic abnormalities in olfactory bulbs. Finally, C-FOS staining was used to monitor neuronal activation of the olfactory system upon odor stimulation. Results: Tbr1 (+/-) mice exhibited smaller olfactory bulbs and anterior commissures, reduced interneuron populations, and an abnormal dendritic morphology of mitral cells in the olfactory bulbs. Tbr1 haploinsufficiency specifically impaired olfactory discrimination but not olfactory sensation. Neuronal activation upon odorant stimulation was reduced in the glomerular layer of Tbr1 (+/-) olfactory bulbs. Furthermore, although the sizes of piriform and perirhinal cortices were not affected by Tbr1 deficiency, neuronal activation was reduced in these two cortical regions in response to odorant stimulation. These results suggest an impairment of neuronal activation in olfactory bulbs and defective connectivity from olfactory bulbs to the upper olfactory system in Tbr1 (+/-) mice. Systemic administration of D-cycloserine, an NMDAR co-agonist, ameliorated olfactory discrimination in Tbr1 (+/-) mice, suggesting that increased neuronal activity has a beneficial effect on Tbr1 deficiency. Conclusions: Tbr1 regulates neural circuits and activity in the olfactory system to control olfaction. Tbr1 (+/-) mice can serve as a suitable model for revealing how an autism causative gene controls neuronal circuits, neural activity, and autism-related behaviors. En ligne : https://dx.doi.org/10.1186/s13229-019-0257-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development / J. ELLEGOOD in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 25 p. Titre : Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development Type de document : Texte imprimé et/ou numérique Auteurs : J. ELLEGOOD, Auteur ; S. P. PETKOVA, Auteur ; A. KINMAN, Auteur ; L. R. QIU, Auteur ; A. ADHIKARI, Auteur ; A. A. WADE, Auteur ; D. FERNANDES, Auteur ; Z. LINDENMAIER, Auteur ; A. CREIGHTON, Auteur ; L. M. J. NUTTER, Auteur ; A. S. NORD, Auteur ; J. L. SILVERMAN, Auteur ; J. P. LERCH, Auteur Article en page(s) : 25 p. Langues : Anglais (eng) Mots-clés : Animals  Behavior, Animal  Brain/diagnostic imaging/growth & development  Exploratory Behavior  Fear  Female  Gait  Haploinsufficiency  Learning  Magnetic Resonance Imaging  Male  Mice, Mutant Strains  Motor Skills  Neurodevelopmental Disorders/diagnostic imaging/psychology  Recognition, Psychology  Social Behavior  Transcription Factors/genetics/metabolism  Vocalization, Animal  Arid1b  Autism  Behavior  Coffin–Siris syndrome  Magnetic resonance imaging  Mouse Index. décimale : PER Périodiques Résumé : BACKGROUND: One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin. AT-rich interactive domain 1B (ARID1B), a chromatin modifier, has been linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs. METHODS: A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays. RESULTS: We validated decreased Arid1b mRNA and protein in Arid1b(+/-) mice, with signatures of increased axonal and synaptic gene expression, decreased transcriptional regulator and RNA processing expression in adult Arid1b(+/-) cerebellum. During neonatal development, Arid1b(+/-) mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex effect was observed neuroanatomically throughout development. Behaviorally, as adults, Arid1b(+/-) mice showed low motor skills in open field exploration and normal three-chambered approach. Arid1b(+/-) mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviors were observed. Brains of adult Arid1b(+/-) mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans. LIMITATIONS: The behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b. CONCLUSIONS: This study represents a full validation and investigation of a novel model of Arid1b(+/-) haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs. En ligne : http://dx.doi.org/10.1186/s13229-021-00432-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Neuroanatomy and behavior in mice with a haploinsufficiency of AT-rich interactive domain 1B (ARID1B) throughout development [Texte imprimé et/ou numérique] / J. ELLEGOOD, Auteur ; S. P. PETKOVA, Auteur ; A. KINMAN, Auteur ; L. R. QIU, Auteur ; A. ADHIKARI, Auteur ; A. A. WADE, Auteur ; D. FERNANDES, Auteur ; Z. LINDENMAIER, Auteur ; A. CREIGHTON, Auteur ; L. M. J. NUTTER, Auteur ; A. S. NORD, Auteur ; J. L. SILVERMAN, Auteur ; J. P. LERCH, Auteur . - 25 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 25 p. Mots-clés : Animals  Behavior, Animal  Brain/diagnostic imaging/growth & development  Exploratory Behavior  Fear  Female  Gait  Haploinsufficiency  Learning  Magnetic Resonance Imaging  Male  Mice, Mutant Strains  Motor Skills  Neurodevelopmental Disorders/diagnostic imaging/psychology  Recognition, Psychology  Social Behavior  Transcription Factors/genetics/metabolism  Vocalization, Animal  Arid1b  Autism  Behavior  Coffin–Siris syndrome  Magnetic resonance imaging  Mouse Index. décimale : PER Périodiques Résumé : BACKGROUND: One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification and the genes that regulate chromatin. AT-rich interactive domain 1B (ARID1B), a chromatin modifier, has been linked to autism spectrum disorder and to affect rare and inherited genetic variation in a broad set of NDDs. METHODS: A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioral and transcriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioral testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviors, seizure susceptibility, and general milestones delays. RESULTS: We validated decreased Arid1b mRNA and protein in Arid1b(+/-) mice, with signatures of increased axonal and synaptic gene expression, decreased transcriptional regulator and RNA processing expression in adult Arid1b(+/-) cerebellum. During neonatal development, Arid1b(+/-) mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex effect was observed neuroanatomically throughout development. Behaviorally, as adults, Arid1b(+/-) mice showed low motor skills in open field exploration and normal three-chambered approach. Arid1b(+/-) mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviors were observed. Brains of adult Arid1b(+/-) mice had a smaller cerebellum and a larger hippocampus and corpus callosum. The corpus callosum increase seen here contrasts previous reports which highlight losses in corpus callosum volume in mice and humans. LIMITATIONS: The behavior and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioral findings, and the transcriptomic analysis was exploratory, with no validation of altered expression beyond Arid1b. CONCLUSIONS: This study represents a full validation and investigation of a novel model of Arid1b(+/-) haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs. En ligne : http://dx.doi.org/10.1186/s13229-021-00432-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

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