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

Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice / Stijn VAN DE SOMPELE ; Clemence LIGNEUL ; Camille CHATELAIN ; Christophe BARREA ; Jason P LERCH ; Beatrice M FILIPPI ; Serpil ALKAN ; Elfride DE BAERE ; Jamie JOHNSTON ; Steven J. CLAPCOTE in Molecular Autism, 16 (2025)  

Public ISBD [article]  inMolecular Autism > 16 (2025) . - 14 Titre : Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice Type de document : texte imprimé Auteurs : Stijn VAN DE SOMPELE, Auteur ; Clemence LIGNEUL, Auteur ; Camille CHATELAIN, Auteur ; Christophe BARREA, Auteur ; Jason P LERCH, Auteur ; Beatrice M FILIPPI, Auteur ; Serpil ALKAN, Auteur ; Elfride DE BAERE, Auteur ; Jamie JOHNSTON, Auteur ; Steven J. CLAPCOTE, Auteur Article en page(s) : 14 Langues : Anglais (eng) Mots-clés : Animals  Humans  Male  Female  Mice  Autistic Disorder/genetics  Alleles  Intellectual Disability/genetics  Pedigree  Autism Spectrum Disorder/genetics  Child  Phenotype  Behavior, Animal  Membrane Proteins/genetics  Social Behavior  Mutation  Adult  Child, Preschool  DNA-Binding Proteins  Autism spectrum disorder  Intellectual disability  Olfactory behavior  Pdzd8  Social discrimination  approved by Ghent University Ethical Committee. The affected individuals were  recruited to the study with the informed consent of their mother using a process  that adhered to the tenets of the Declaration of Helsinki. The mouse experiments  were conducted in compliance with the UK Animals (Scientific Procedures) Act 1986  under UK Home Office licences and approved by the Animal Welfare and Ethical  Review Body at the University of Leeds. Consent for publication: Written consent  for publication of case reports and images pertaining to the affected individuals  was obtained from their mother. Competing interests: The authors declare no  competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Intellectual developmental disorder with autism and dysmorphic facies (IDDADF) is a rare syndromic intellectual disability (ID) caused by homozygous disruption of PDZD8 (PDZ domain-containing protein 8), an integral endoplasmic reticulum (ER) protein. All four previously identified IDDADF cases exhibit autistic behavior, with autism spectrum disorder (ASD) diagnosed in three cases. To determine whether autistic behavior is a common outcome of PDZD8 disruption, we studied a third family with biallelic mutation of PDZD8 (family C) and further characterized PDZD8-deficient (Pdzd8(tm1b)) mice that exhibit stereotyped motor behavior relevant to ASD. METHODS: Homozygosity mapping, whole-exome sequencing, and cosegregation analysis were used to identify the PDZD8 variant responsible for IDDADF, including diagnoses of ASD, in consanguineous family C. To assess the in vivo effect of PDZD8 disruption on social responses and related phenotypes, behavioral, structural magnetic resonance imaging, and microscopy analyses were conducted on the Pdzd8(tm1b) mouse line. Metabolic activity was profiled using sealed metabolic cages. RESULTS: The discovery of a third family with IDDADF caused by biallelic disruption of PDZD8 permitted identification of a core clinical phenotype consisting of developmental delay, ID, autism, and facial dysmorphism. In addition to impairments in social recognition and social odor discrimination, Pdzd8(tm1b) mice exhibit increases in locomotor activity (dark phase only) and metabolic rate (both lights-on and dark phases), and decreased plasma triglyceride in males. In the brain, Pdzd8(tm1b) mice exhibit increased levels of accessory olfactory bulb volume, primary olfactory cortex volume, dendritic spine density, and ER stress- and mitochondrial fusion-related transcripts, as well as decreased levels of cerebellar nuclei volume and adult neurogenesis. LIMITATIONS: The total number of known cases of PDZD8-related IDDADF remains low. Some mouse experiments in the study did not use balanced numbers of males and females. The assessment of ER stress and mitochondrial fusion markers did not extend beyond mRNA levels. CONCLUSIONS: Our finding that the Pdzd8(tm1b) mouse model and all six known cases of IDDADF exhibit autistic behavior, with ASD diagnosed in five cases, identifies this trait as a common outcome of biallelic disruption of PDZD8 in humans and mice. Other abnormalities exhibited by Pdzd8(tm1b) mice suggest that the range of comorbidities associated with PDZD8 deficiency may be wider than presently recognized. En ligne : https://dx.doi.org/10.1186/s13229-025-00650-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555 [article] Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice [texte imprimé] / Stijn VAN DE SOMPELE, Auteur ; Clemence LIGNEUL, Auteur ; Camille CHATELAIN, Auteur ; Christophe BARREA, Auteur ; Jason P LERCH, Auteur ; Beatrice M FILIPPI, Auteur ; Serpil ALKAN, Auteur ; Elfride DE BAERE, Auteur ; Jamie JOHNSTON, Auteur ; Steven J. CLAPCOTE, Auteur . - 14. Langues : Anglais (eng) in Molecular Autism > 16 (2025) . - 14 Mots-clés : Animals  Humans  Male  Female  Mice  Autistic Disorder/genetics  Alleles  Intellectual Disability/genetics  Pedigree  Autism Spectrum Disorder/genetics  Child  Phenotype  Behavior, Animal  Membrane Proteins/genetics  Social Behavior  Mutation  Adult  Child, Preschool  DNA-Binding Proteins  Autism spectrum disorder  Intellectual disability  Olfactory behavior  Pdzd8  Social discrimination  approved by Ghent University Ethical Committee. The affected individuals were  recruited to the study with the informed consent of their mother using a process  that adhered to the tenets of the Declaration of Helsinki. The mouse experiments  were conducted in compliance with the UK Animals (Scientific Procedures) Act 1986  under UK Home Office licences and approved by the Animal Welfare and Ethical  Review Body at the University of Leeds. Consent for publication: Written consent  for publication of case reports and images pertaining to the affected individuals  was obtained from their mother. Competing interests: The authors declare no  competing interests. Index. décimale : PER Périodiques Résumé : BACKGROUND: Intellectual developmental disorder with autism and dysmorphic facies (IDDADF) is a rare syndromic intellectual disability (ID) caused by homozygous disruption of PDZD8 (PDZ domain-containing protein 8), an integral endoplasmic reticulum (ER) protein. All four previously identified IDDADF cases exhibit autistic behavior, with autism spectrum disorder (ASD) diagnosed in three cases. To determine whether autistic behavior is a common outcome of PDZD8 disruption, we studied a third family with biallelic mutation of PDZD8 (family C) and further characterized PDZD8-deficient (Pdzd8(tm1b)) mice that exhibit stereotyped motor behavior relevant to ASD. METHODS: Homozygosity mapping, whole-exome sequencing, and cosegregation analysis were used to identify the PDZD8 variant responsible for IDDADF, including diagnoses of ASD, in consanguineous family C. To assess the in vivo effect of PDZD8 disruption on social responses and related phenotypes, behavioral, structural magnetic resonance imaging, and microscopy analyses were conducted on the Pdzd8(tm1b) mouse line. Metabolic activity was profiled using sealed metabolic cages. RESULTS: The discovery of a third family with IDDADF caused by biallelic disruption of PDZD8 permitted identification of a core clinical phenotype consisting of developmental delay, ID, autism, and facial dysmorphism. In addition to impairments in social recognition and social odor discrimination, Pdzd8(tm1b) mice exhibit increases in locomotor activity (dark phase only) and metabolic rate (both lights-on and dark phases), and decreased plasma triglyceride in males. In the brain, Pdzd8(tm1b) mice exhibit increased levels of accessory olfactory bulb volume, primary olfactory cortex volume, dendritic spine density, and ER stress- and mitochondrial fusion-related transcripts, as well as decreased levels of cerebellar nuclei volume and adult neurogenesis. LIMITATIONS: The total number of known cases of PDZD8-related IDDADF remains low. Some mouse experiments in the study did not use balanced numbers of males and females. The assessment of ER stress and mitochondrial fusion markers did not extend beyond mRNA levels. CONCLUSIONS: Our finding that the Pdzd8(tm1b) mouse model and all six known cases of IDDADF exhibit autistic behavior, with ASD diagnosed in five cases, identifies this trait as a common outcome of biallelic disruption of PDZD8 in humans and mice. Other abnormalities exhibited by Pdzd8(tm1b) mice suggest that the range of comorbidities associated with PDZD8 deficiency may be wider than presently recognized. En ligne : https://dx.doi.org/10.1186/s13229-025-00650-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555

The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in Nrxn2 deletion mice / E. PERVOLARAKI in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 8 p. Titre : The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in Nrxn2 deletion mice Type de document : texte imprimé Auteurs : E. PERVOLARAKI, Auteur ; A. L. TYSON, Auteur ; F. PIBIRI, Auteur ; S. L. POULTER, Auteur ; A. C. REICHELT, Auteur ; R. J. RODGERS, Auteur ; Steven J. CLAPCOTE, Auteur ; C. LEVER, Auteur ; L. C. ANDREAE, Auteur ; J. DACHTLER, Auteur Article en page(s) : 8 p. Langues : Anglais (eng) Mots-clés : *Autism  *Axons  *clarity  *Diffusion  *Imaging  *mri  *Social  *Structure  in accordance with the Animals (Scientific Procedures) Act 1986, and with the  approval of the University of Leeds and Durham University Animal Ethical and  Welfare Review Boards.Not applicableThe authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Of the many genetic mutations known to increase the risk of autism spectrum disorder, a large proportion cluster upon synaptic proteins. One such family of presynaptic proteins are the neurexins (NRXN), and recent genetic and mouse evidence has suggested a causative role for NRXN2 in generating altered social behaviours. Autism has been conceptualised as a disorder of atypical connectivity, yet how single-gene mutations affect such connectivity remains under-explored. To attempt to address this, we have developed a quantitative analysis of microstructure and structural connectivity leveraging diffusion tensor MRI (DTI) with high-resolution 3D imaging in optically cleared (CLARITY) brain tissue in the same mouse, applied here to the Nrxn2alpha knockout (KO) model. Methods: Fixed brains of Nrxn2alpha KO mice underwent DTI using 9.4 T MRI, and diffusion properties of socially relevant brain regions were quantified. The same tissue was then subjected to CLARITY to immunolabel axons and cell bodies, which were also quantified. Results: DTI revealed increases in fractional anisotropy in the amygdala (including the basolateral nuclei), the anterior cingulate cortex, the orbitofrontal cortex and the hippocampus. Axial diffusivity of the anterior cingulate cortex and orbitofrontal cortex was significantly increased in Nrxn2alpha KO mice, as were tracts between the amygdala and the orbitofrontal cortex. Using CLARITY, we find significantly altered axonal orientation in the amygdala, orbitofrontal cortex and the anterior cingulate cortex, which was unrelated to cell density. Conclusions: Our findings demonstrate that deleting a single neurexin gene (Nrxn2alpha) induces atypical structural connectivity within socially relevant brain regions. More generally, our combined within-subject DTI and CLARITY approach presents a new, more sensitive method of revealing hitherto undetectable differences in the autistic brain. En ligne : https://dx.doi.org/10.1186/s13229-019-0261-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in Nrxn2 deletion mice [texte imprimé] / E. PERVOLARAKI, Auteur ; A. L. TYSON, Auteur ; F. PIBIRI, Auteur ; S. L. POULTER, Auteur ; A. C. REICHELT, Auteur ; R. J. RODGERS, Auteur ; Steven J. CLAPCOTE, Auteur ; C. LEVER, Auteur ; L. C. ANDREAE, Auteur ; J. DACHTLER, Auteur . - 8 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 8 p. Mots-clés : *Autism  *Axons  *clarity  *Diffusion  *Imaging  *mri  *Social  *Structure  in accordance with the Animals (Scientific Procedures) Act 1986, and with the  approval of the University of Leeds and Durham University Animal Ethical and  Welfare Review Boards.Not applicableThe authors declare that they have no  competing interests.Springer Nature remains neutral with regard to jurisdictional  claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Of the many genetic mutations known to increase the risk of autism spectrum disorder, a large proportion cluster upon synaptic proteins. One such family of presynaptic proteins are the neurexins (NRXN), and recent genetic and mouse evidence has suggested a causative role for NRXN2 in generating altered social behaviours. Autism has been conceptualised as a disorder of atypical connectivity, yet how single-gene mutations affect such connectivity remains under-explored. To attempt to address this, we have developed a quantitative analysis of microstructure and structural connectivity leveraging diffusion tensor MRI (DTI) with high-resolution 3D imaging in optically cleared (CLARITY) brain tissue in the same mouse, applied here to the Nrxn2alpha knockout (KO) model. Methods: Fixed brains of Nrxn2alpha KO mice underwent DTI using 9.4 T MRI, and diffusion properties of socially relevant brain regions were quantified. The same tissue was then subjected to CLARITY to immunolabel axons and cell bodies, which were also quantified. Results: DTI revealed increases in fractional anisotropy in the amygdala (including the basolateral nuclei), the anterior cingulate cortex, the orbitofrontal cortex and the hippocampus. Axial diffusivity of the anterior cingulate cortex and orbitofrontal cortex was significantly increased in Nrxn2alpha KO mice, as were tracts between the amygdala and the orbitofrontal cortex. Using CLARITY, we find significantly altered axonal orientation in the amygdala, orbitofrontal cortex and the anterior cingulate cortex, which was unrelated to cell density. Conclusions: Our findings demonstrate that deleting a single neurexin gene (Nrxn2alpha) induces atypical structural connectivity within socially relevant brain regions. More generally, our combined within-subject DTI and CLARITY approach presents a new, more sensitive method of revealing hitherto undetectable differences in the autistic brain. En ligne : https://dx.doi.org/10.1186/s13229-019-0261-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

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