127 recherche sur le mot-clé 'Animals'

Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development / Shaun HURLEY in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 16 p. Titre : Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development Type de document : texte imprimé Auteurs : Shaun HURLEY, Auteur ; Conor MOHAN, Auteur ; Philipp SUETTERLIN, Auteur ; Robert ELLINGFORD, Auteur ; Kimberley L.H. RIEGMAN, Auteur ; Jacob ELLEGOOD, Auteur ; Angela CARUSO, Auteur ; Caterina MICHETTI, Auteur ; Olivier BROCK, Auteur ; Romy EVANS, Auteur ; Fabrizio RUDARI, Auteur ; Alessio DELOGU, Auteur ; Maria Luisa SCATTONI, Auteur ; Jason P. LERCH, Auteur ; Cathy FERNANDES, Auteur ; M. Albert BASSON, Auteur Article en page(s) : 16 p. Langues : Anglais (eng) Mots-clés : Animals  Animals, Newborn  Autistic Disorder/genetics  Behavior, Animal  Brain/diagnostic imaging/embryology/growth & development  Cell Proliferation  DNA-Binding Proteins/deficiency/genetics  Disease Models, Animal  Female  Gene Expression Regulation, Developmental  Mice, Transgenic  Phenotype  Pregnancy  Stem Cells  Tumor Suppressor Protein p53/genetics  Apoptosis  Autism  Chd8  Chromatin  Conditional knockout  Cortex  Gene expression  Hypomorph  Intermediate progenitor  Mouse  Neural progenitor  Proliferation  Tbr2  p53  Pathways plc. This work is unrelated to COMPASS Pathways plc. No other competing  interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. METHODS: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. RESULTS: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. CONCLUSIONS: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work. En ligne : http://dx.doi.org/10.1186/s13229-020-00409-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development [texte imprimé] / Shaun HURLEY, Auteur ; Conor MOHAN, Auteur ; Philipp SUETTERLIN, Auteur ; Robert ELLINGFORD, Auteur ; Kimberley L.H. RIEGMAN, Auteur ; Jacob ELLEGOOD, Auteur ; Angela CARUSO, Auteur ; Caterina MICHETTI, Auteur ; Olivier BROCK, Auteur ; Romy EVANS, Auteur ; Fabrizio RUDARI, Auteur ; Alessio DELOGU, Auteur ; Maria Luisa SCATTONI, Auteur ; Jason P. LERCH, Auteur ; Cathy FERNANDES, Auteur ; M. Albert BASSON, Auteur . - 16 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 16 p. Mots-clés : Animals  Animals, Newborn  Autistic Disorder/genetics  Behavior, Animal  Brain/diagnostic imaging/embryology/growth & development  Cell Proliferation  DNA-Binding Proteins/deficiency/genetics  Disease Models, Animal  Female  Gene Expression Regulation, Developmental  Mice, Transgenic  Phenotype  Pregnancy  Stem Cells  Tumor Suppressor Protein p53/genetics  Apoptosis  Autism  Chd8  Chromatin  Conditional knockout  Cortex  Gene expression  Hypomorph  Intermediate progenitor  Mouse  Neural progenitor  Proliferation  Tbr2  p53  Pathways plc. This work is unrelated to COMPASS Pathways plc. No other competing  interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. METHODS: To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. RESULTS: Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. CONCLUSIONS: Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work. En ligne : http://dx.doi.org/10.1186/s13229-020-00409-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

Distinct early development trajectories in Nf1(±) and Tsc2(±) mouse models of autism / Helena FERREIRA in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : Distinct early development trajectories in Nf1(±) and Tsc2(±) mouse models of autism Type de document : texte imprimé Auteurs : Helena FERREIRA, Auteur ; Sofia SANTOS, Auteur ; João MARTINS, Auteur ; Miguel CASTELO-BRANCO, Auteur ; Joana GONÇALVES, Auteur Langues : Anglais (eng) Mots-clés : Animals  Disease Models, Animal  Tuberous Sclerosis Complex 2 Protein/genetics  Male  Female  Mice  Vocalization, Animal/physiology  Autism Spectrum Disorder/genetics/physiopathology  Neurofibromatosis 1/genetics/physiopathology  Neurofibromin 1/genetics  Animals, Newborn  Tuberous Sclerosis/genetics  Sex Characteristics  Maternal Deprivation  Mice, Inbred C57BL  Asd  Developmental milestones  Neurofibromatosis type 1  Tuberous sclerosis complex 2  Ultrasonic vocalizations  following the European Union Council Directive (2010/63/EU), National  Regulations, and ORBEA board of ICNAS (1/2017). Consent for publication: Not  applicable. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, and repetitive behaviors. Males are three times more likely to be diagnosed with ASD than females, and sex-dependent alterations in behavior and communication have been reported both in clinical and animal research. Animal models are useful for understanding ASD-related manifestations and their associated neurobiological mechanisms. However, even though ASD is diagnosed during childhood, relatively few animal studies have focused on neonatal development. METHODS: Here, we performed a detailed analysis of neonatal developmental milestones and maternal separation-induced ultrasonic vocalizations (USVs) in two genetic animal models of ASD, neurofibromatosis type 1 (Nf1(±)) and tuberous sclerosis complex 2 (Tsc2(±)). RESULTS: Nf1(±) and Tsc2(±) mice display strikingly distinct developmental profiles regarding motor, strength, and coordination skills. Nf1(±) mouse pups mostly show genotype-related differences, whereas Tsc2(±) mouse pups mainly present sexual dimorphisms. Furthermore, we found several differences regarding the number of USVs, frequency modulation, and temporal and spectral profile. Importantly, Nf1(±) animals tend to present sex- and genotype-dependent differences earlier than the Tsc2(±) mouse pups, suggesting distinct developmental curves between these two animal models. CONCLUSIONS: This study provides a nuanced understanding of how these two ASD models differ in their developmental trajectories. It underscores the importance of studying sex differences and early-life developmental markers, as these could offer crucial insights into ASD's progression and neurobiology. The distinct profiles of these models may help guide more targeted therapeutic strategies in the future. En ligne : https://dx.doi.org/10.1186/s11689-025-09624-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Distinct early development trajectories in Nf1(±) and Tsc2(±) mouse models of autism [texte imprimé] / Helena FERREIRA, Auteur ; Sofia SANTOS, Auteur ; João MARTINS, Auteur ; Miguel CASTELO-BRANCO, Auteur ; Joana GONÇALVES, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Animals  Disease Models, Animal  Tuberous Sclerosis Complex 2 Protein/genetics  Male  Female  Mice  Vocalization, Animal/physiology  Autism Spectrum Disorder/genetics/physiopathology  Neurofibromatosis 1/genetics/physiopathology  Neurofibromin 1/genetics  Animals, Newborn  Tuberous Sclerosis/genetics  Sex Characteristics  Maternal Deprivation  Mice, Inbred C57BL  Asd  Developmental milestones  Neurofibromatosis type 1  Tuberous sclerosis complex 2  Ultrasonic vocalizations  following the European Union Council Directive (2010/63/EU), National  Regulations, and ORBEA board of ICNAS (1/2017). Consent for publication: Not  applicable. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and interaction, and repetitive behaviors. Males are three times more likely to be diagnosed with ASD than females, and sex-dependent alterations in behavior and communication have been reported both in clinical and animal research. Animal models are useful for understanding ASD-related manifestations and their associated neurobiological mechanisms. However, even though ASD is diagnosed during childhood, relatively few animal studies have focused on neonatal development. METHODS: Here, we performed a detailed analysis of neonatal developmental milestones and maternal separation-induced ultrasonic vocalizations (USVs) in two genetic animal models of ASD, neurofibromatosis type 1 (Nf1(±)) and tuberous sclerosis complex 2 (Tsc2(±)). RESULTS: Nf1(±) and Tsc2(±) mice display strikingly distinct developmental profiles regarding motor, strength, and coordination skills. Nf1(±) mouse pups mostly show genotype-related differences, whereas Tsc2(±) mouse pups mainly present sexual dimorphisms. Furthermore, we found several differences regarding the number of USVs, frequency modulation, and temporal and spectral profile. Importantly, Nf1(±) animals tend to present sex- and genotype-dependent differences earlier than the Tsc2(±) mouse pups, suggesting distinct developmental curves between these two animal models. CONCLUSIONS: This study provides a nuanced understanding of how these two ASD models differ in their developmental trajectories. It underscores the importance of studying sex differences and early-life developmental markers, as these could offer crucial insights into ASD's progression and neurobiology. The distinct profiles of these models may help guide more targeted therapeutic strategies in the future. En ligne : https://dx.doi.org/10.1186/s11689-025-09624-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Firing activity of locus coeruleus noradrenergic neurons decreases in necdin-deficient mice, an animal model of Prader-Willi syndrome / Rui-Ni WU in Journal of Neurodevelopmental Disorders, 12 (2020)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 12 (2020) Titre : Firing activity of locus coeruleus noradrenergic neurons decreases in necdin-deficient mice, an animal model of Prader-Willi syndrome Type de document : texte imprimé Auteurs : Rui-Ni WU, Auteur ; Wei-Chen HUNG, Auteur ; Ching-Tsuey CHEN, Auteur ; Li-Ping TSAI, Auteur ; Wen-Sung LAI, Auteur ; Ming-Yuan MIN, Auteur ; Shi-Bing WONG, Auteur Langues : Anglais (eng) Mots-clés : Adrenergic Neurons/metabolism  Animals  Animals, Newborn  Disease Models, Animal  Female  Gene Expression Regulation, Developmental  Locus Coeruleus/metabolism  Mice  Nerve Tissue Proteins  Nuclear Proteins  Prader-Willi Syndrome/metabolism  A-type potassium current  Hypercapnia  Hypotonia  Locus coeruleus  Necdin  Prader–Willi syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by multiple respiratory, cognitive, endocrine, and behavioral symptoms, such as central apnea, intellectual disabilities, exaggerated stress responses, and temper tantrums. The locus coeruleus noradrenergic system (LC-NE) modulates a diverse range of behaviors, including arousal, learning, pain modulation, and stress-induced negative affective states, which are possibly correlated with the pathogenesis of PWS phenotypes. Therefore, we evaluated the LC-NE neuronal activity of necdin-deficient mice, an animal model of PWS. METHODS: Heterozygous necdin-deficient mice (B6.Cg-Ndn(tm1ky)) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygotes (+m/-p) animals, which were examined of LC-NE neuronal activity, developmental reflexes, and plethysmography. RESULTS: On slice electrophysiology, LC-NE neurons of Ndn(tm1ky) mice with necdin deficiency showed significantly decreased spontaneous activities and impaired excitability, which was mediated by enhanced A-type voltage-dependent potassium currents. Ndn(tm1ky) mice also exhibited the neonatal phenotypes of PWS, such as hypotonia and blunt respiratory responses to hypercapnia. CONCLUSIONS: LC-NE neuronal firing activity decreased in necdin-deficient mice, suggesting that LC, the primary source of norepinephrine in the central nervous system, is possibly involved in PWS pathogenesis. En ligne : https://dx.doi.org/10.1186/s11689-020-09323-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Firing activity of locus coeruleus noradrenergic neurons decreases in necdin-deficient mice, an animal model of Prader-Willi syndrome [texte imprimé] / Rui-Ni WU, Auteur ; Wei-Chen HUNG, Auteur ; Ching-Tsuey CHEN, Auteur ; Li-Ping TSAI, Auteur ; Wen-Sung LAI, Auteur ; Ming-Yuan MIN, Auteur ; Shi-Bing WONG, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 12 (2020) Mots-clés : Adrenergic Neurons/metabolism  Animals  Animals, Newborn  Disease Models, Animal  Female  Gene Expression Regulation, Developmental  Locus Coeruleus/metabolism  Mice  Nerve Tissue Proteins  Nuclear Proteins  Prader-Willi Syndrome/metabolism  A-type potassium current  Hypercapnia  Hypotonia  Locus coeruleus  Necdin  Prader–Willi syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by multiple respiratory, cognitive, endocrine, and behavioral symptoms, such as central apnea, intellectual disabilities, exaggerated stress responses, and temper tantrums. The locus coeruleus noradrenergic system (LC-NE) modulates a diverse range of behaviors, including arousal, learning, pain modulation, and stress-induced negative affective states, which are possibly correlated with the pathogenesis of PWS phenotypes. Therefore, we evaluated the LC-NE neuronal activity of necdin-deficient mice, an animal model of PWS. METHODS: Heterozygous necdin-deficient mice (B6.Cg-Ndn(tm1ky)) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygotes (+m/-p) animals, which were examined of LC-NE neuronal activity, developmental reflexes, and plethysmography. RESULTS: On slice electrophysiology, LC-NE neurons of Ndn(tm1ky) mice with necdin deficiency showed significantly decreased spontaneous activities and impaired excitability, which was mediated by enhanced A-type voltage-dependent potassium currents. Ndn(tm1ky) mice also exhibited the neonatal phenotypes of PWS, such as hypotonia and blunt respiratory responses to hypercapnia. CONCLUSIONS: LC-NE neuronal firing activity decreased in necdin-deficient mice, suggesting that LC, the primary source of norepinephrine in the central nervous system, is possibly involved in PWS pathogenesis. En ligne : https://dx.doi.org/10.1186/s11689-020-09323-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

Altered medial prefrontal cortex and dorsal raphé activity predict genotype and correlate with abnormal learning behavior in a mouse model of autism-associated 2p16.3 deletion / Rebecca B. HUGHES in Autism Research, 15-4 (April 2022)  

Public ISBD [article]  inAutism Research > 15-4 (April 2022) . - p.614-627 Titre : Altered medial prefrontal cortex and dorsal raphé activity predict genotype and correlate with abnormal learning behavior in a mouse model of autism-associated 2p16.3 deletion Type de document : texte imprimé Auteurs : Rebecca B. HUGHES, Auteur ; Jayde WHITTINGHAM-DOWD, Auteur ; Steven J. CLAPCOTE, Auteur ; Susan J. BROUGHTON, Auteur ; Neil DAWSON, Auteur Article en page(s) : p.614-627 Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Autistic Disorder  Disease Models, Animal  Dorsal Raphe Nucleus  Genotype  Humans  Male  Mice  Prefrontal Cortex/diagnostic imaging  Reversal Learning  cognitive neuroscience  copy number variation/copy number variants  frontal lobe  genotype-phenotype correlation  imaging genetics  mouse models  serotonin Index. décimale : PER Périodiques Résumé : 2p16.3 deletion, involving NEUREXIN1 (NRXN1) heterozygous deletion, substantially increases the risk of developing autism and other neurodevelopmental disorders. We have a poor understanding of how NRXN1 heterozygosity impacts on brain function and cognition to increase the risk of developing the disorder. Here we characterize the impact of Nrxn1 heterozygosity on cerebral metabolism, in mice, using (14) C-2-deoxyglucose imaging. We also assess performance in an olfactory-based discrimination and reversal learning (OB-DaRL) task and locomotor activity. We use decision tree classifiers to test the predictive relationship between cerebral metabolism and Nrxn1 genotype. Our data show that Nrxn1 heterozygosity induces prefrontal cortex (medial prelimbic cortex, mPrL) hypometabolism and a contrasting dorsal raphé nucleus (DRN) hypermetabolism. Metabolism in these regions allows for the predictive classification of Nrxn1 genotype. Consistent with reduced mPrL glucose utilization, prefrontal cortex insulin receptor signaling is decreased in Nrxn1 (+/-) mice. Behaviorally, Nrxn1 (+/-) mice show enhanced learning of a novel discrimination, impaired reversal learning and an increased latency to make correct choices. In addition, male Nrxn1 (+/-) mice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhanced novel odor discrimination seen in Nrxn1 (+/-) mice, while DRN hypermetabolism contributes to their increased latency in making correct choices. The data show that Nrxn1 heterozygosity impacts on prefrontal cortex and serotonin system function, which contribute to the cognitive alterations seen in these animals. The data suggest that Nrxn1 (+/-) mice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion. LAY SUMMARY: Deletion of the chromosomal region 2p16.3, involving reduced NEUREXIN1 gene expression, dramatically increases the risk of developing autism. Here, we show that reduced Neurexin1 expression, in mice, impacts on the prefrontal cortex and impairs cognitive flexibility. The data suggest that 2p16.3 deletion increases the risk of developing autism by impacting on the prefrontal cortex. Mice with the deletion are a useful model for testing new drugs to treat the cognitive flexibility problems experienced by people with autism. En ligne : https://dx.doi.org/10.1002/aur.2685 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473 [article] Altered medial prefrontal cortex and dorsal raphé activity predict genotype and correlate with abnormal learning behavior in a mouse model of autism-associated 2p16.3 deletion [texte imprimé] / Rebecca B. HUGHES, Auteur ; Jayde WHITTINGHAM-DOWD, Auteur ; Steven J. CLAPCOTE, Auteur ; Susan J. BROUGHTON, Auteur ; Neil DAWSON, Auteur . - p.614-627. Langues : Anglais (eng) in Autism Research > 15-4 (April 2022) . - p.614-627 Mots-clés : Animals  Autism Spectrum Disorder/genetics  Autistic Disorder  Disease Models, Animal  Dorsal Raphe Nucleus  Genotype  Humans  Male  Mice  Prefrontal Cortex/diagnostic imaging  Reversal Learning  cognitive neuroscience  copy number variation/copy number variants  frontal lobe  genotype-phenotype correlation  imaging genetics  mouse models  serotonin Index. décimale : PER Périodiques Résumé : 2p16.3 deletion, involving NEUREXIN1 (NRXN1) heterozygous deletion, substantially increases the risk of developing autism and other neurodevelopmental disorders. We have a poor understanding of how NRXN1 heterozygosity impacts on brain function and cognition to increase the risk of developing the disorder. Here we characterize the impact of Nrxn1 heterozygosity on cerebral metabolism, in mice, using (14) C-2-deoxyglucose imaging. We also assess performance in an olfactory-based discrimination and reversal learning (OB-DaRL) task and locomotor activity. We use decision tree classifiers to test the predictive relationship between cerebral metabolism and Nrxn1 genotype. Our data show that Nrxn1 heterozygosity induces prefrontal cortex (medial prelimbic cortex, mPrL) hypometabolism and a contrasting dorsal raphé nucleus (DRN) hypermetabolism. Metabolism in these regions allows for the predictive classification of Nrxn1 genotype. Consistent with reduced mPrL glucose utilization, prefrontal cortex insulin receptor signaling is decreased in Nrxn1 (+/-) mice. Behaviorally, Nrxn1 (+/-) mice show enhanced learning of a novel discrimination, impaired reversal learning and an increased latency to make correct choices. In addition, male Nrxn1 (+/-) mice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhanced novel odor discrimination seen in Nrxn1 (+/-) mice, while DRN hypermetabolism contributes to their increased latency in making correct choices. The data show that Nrxn1 heterozygosity impacts on prefrontal cortex and serotonin system function, which contribute to the cognitive alterations seen in these animals. The data suggest that Nrxn1 (+/-) mice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion. LAY SUMMARY: Deletion of the chromosomal region 2p16.3, involving reduced NEUREXIN1 gene expression, dramatically increases the risk of developing autism. Here, we show that reduced Neurexin1 expression, in mice, impacts on the prefrontal cortex and impairs cognitive flexibility. The data suggest that 2p16.3 deletion increases the risk of developing autism by impacting on the prefrontal cortex. Mice with the deletion are a useful model for testing new drugs to treat the cognitive flexibility problems experienced by people with autism. En ligne : https://dx.doi.org/10.1002/aur.2685 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473

Autism-like phenotype across the lifespan of Shank3B-mutant mice of both sexes / Jakub SZABÓ in Journal of Neurodevelopmental Disorders, 17 (2025)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 17 (2025) Titre : Autism-like phenotype across the lifespan of Shank3B-mutant mice of both sexes Type de document : texte imprimé Auteurs : Jakub SZABÓ, Auteur ; Johan FILO, Auteur ; Rebeka DÉMUTHOVÁ, Auteur ; Emese RENCZÉS, Auteur ; Veronika BORBÉLYOVÁ, Auteur ; Daniela OSTATNIKOVA, Auteur ; Peter CELEC, Auteur Langues : Anglais (eng) Mots-clés : Animals  Male  Female  Mice  Nerve Tissue Proteins/genetics  Behavior, Animal/physiology  Phenotype  Disease Models, Animal  Mice, Inbred C57BL  Autism Spectrum Disorder/genetics/physiopathology  Anxiety/genetics/physiopathology  Aging/physiology  Social Behavior  Mice, Knockout  Sex Factors  Microfilament Proteins  Animal model  Phelan-McDermid syndrome  Phenotyping  Symptom development  conducted in accordance with the Slovak national laws and approved by the ethics  committee of the Institute of Molecular Biomedicine. Consent for publication: Not  applicable. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: High heritability (80-90%) of the autism spectrum disorder (ASD) and sex-biased incidence (3-4 times more boys than girls) suggest the roles of genetic predisposition and sex in the etiopathogenesis of the disorder. As ASD is commonly diagnosed in early childhood, most of the research is focused on children, yet animal research predominantly uses adult-aged animals. The effect of aging on the core and secondary ASD symptomatology is understudied, both in patients and animal models of ASD. METHODS: To investigate the effect of aging on sociability, repetitive behavior, exploration, locomotor activity, anxiety-like behavior, and object-avoidance behavior, behavioral phenotyping was conducted in Shank3B(-/-) (n = 67) and C57BL/6J wild-type (WT, n = 68) mice of both sexes (female n = 70, male n = 65) in adolescence (1-2 months of age, n = 42), adulthood (3-6 months of age, n = 40), and old age (12-18 months of age, n = 53). RESULTS: Social deficits were observed only in old Shank3B(-/-) males. Anxiety-like behavior peaked in adulthood with Shank3B(-/-) mice roughly 20% more anxious than controls. Repetitive grooming and object-induced avoidance behavior were twice more prevalent in Shank3B(-/-) mice consistently across the lifespan. Hypoactivity (20% less distance moved) and reduced exploration (30% less rearing behavior) were recorded in Shank3B(-/-) mice and were more prevalent in female animals (30% less rearing behavior). Data were analyzed using the Three-way ANOVA (genotype, sex, age), followed by a posthoc Bonferroni correction to compare respective subgroups. CONCLUSIONS: Present study shows that aging affects ASD-like phenotype in the Shank3B-mutant mouse model, even though the effect size seems to be small. The mechanisms underlying these partially sex-specific effects should be the subject of further research with potential translational implications. En ligne : https://dx.doi.org/10.1186/s11689-025-09635-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Autism-like phenotype across the lifespan of Shank3B-mutant mice of both sexes [texte imprimé] / Jakub SZABÓ, Auteur ; Johan FILO, Auteur ; Rebeka DÉMUTHOVÁ, Auteur ; Emese RENCZÉS, Auteur ; Veronika BORBÉLYOVÁ, Auteur ; Daniela OSTATNIKOVA, Auteur ; Peter CELEC, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 17 (2025) Mots-clés : Animals  Male  Female  Mice  Nerve Tissue Proteins/genetics  Behavior, Animal/physiology  Phenotype  Disease Models, Animal  Mice, Inbred C57BL  Autism Spectrum Disorder/genetics/physiopathology  Anxiety/genetics/physiopathology  Aging/physiology  Social Behavior  Mice, Knockout  Sex Factors  Microfilament Proteins  Animal model  Phelan-McDermid syndrome  Phenotyping  Symptom development  conducted in accordance with the Slovak national laws and approved by the ethics  committee of the Institute of Molecular Biomedicine. Consent for publication: Not  applicable. Competing interests: The authors declare no competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: High heritability (80-90%) of the autism spectrum disorder (ASD) and sex-biased incidence (3-4 times more boys than girls) suggest the roles of genetic predisposition and sex in the etiopathogenesis of the disorder. As ASD is commonly diagnosed in early childhood, most of the research is focused on children, yet animal research predominantly uses adult-aged animals. The effect of aging on the core and secondary ASD symptomatology is understudied, both in patients and animal models of ASD. METHODS: To investigate the effect of aging on sociability, repetitive behavior, exploration, locomotor activity, anxiety-like behavior, and object-avoidance behavior, behavioral phenotyping was conducted in Shank3B(-/-) (n = 67) and C57BL/6J wild-type (WT, n = 68) mice of both sexes (female n = 70, male n = 65) in adolescence (1-2 months of age, n = 42), adulthood (3-6 months of age, n = 40), and old age (12-18 months of age, n = 53). RESULTS: Social deficits were observed only in old Shank3B(-/-) males. Anxiety-like behavior peaked in adulthood with Shank3B(-/-) mice roughly 20% more anxious than controls. Repetitive grooming and object-induced avoidance behavior were twice more prevalent in Shank3B(-/-) mice consistently across the lifespan. Hypoactivity (20% less distance moved) and reduced exploration (30% less rearing behavior) were recorded in Shank3B(-/-) mice and were more prevalent in female animals (30% less rearing behavior). Data were analyzed using the Three-way ANOVA (genotype, sex, age), followed by a posthoc Bonferroni correction to compare respective subgroups. CONCLUSIONS: Present study shows that aging affects ASD-like phenotype in the Shank3B-mutant mouse model, even though the effect size seems to be small. The mechanisms underlying these partially sex-specific effects should be the subject of further research with potential translational implications. En ligne : https://dx.doi.org/10.1186/s11689-025-09635-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

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