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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)
[article]
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 et/ou numérique 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
in Autism Research > 15-4 (April 2022) . - p.614-627[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 et/ou numérique] / 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 Differential effects by sex with Kmt5b loss / R. N. WICKRAMASEKARA in Autism Research, 14-8 (August 2021)
[article]
Titre : Differential effects by sex with Kmt5b loss Type de document : Texte imprimé et/ou numérique Auteurs : R. N. WICKRAMASEKARA, Auteur ; B. ROBERTSON, Auteur ; J. HULEN, Auteur ; J. HALLGREN, Auteur ; H. A. F. STESSMAN, Auteur Article en page(s) : p.1554-1571 Langues : Anglais (eng) Mots-clés : Adult Animals Anxiety/genetics Autism Spectrum Disorder/genetics Disease Models, Animal Fear Female Grooming Humans Male Mice Mice, Knockout Social Behavior Young Adult genetics genotype-phenotype correlation mouse models Index. décimale : PER Périodiques Résumé : Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in genetic studies of neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet, its role in the brain is not known. The goal of this work was to neurodevelopmentally characterize the effect(s) of KMT5B haploinsufficiency using a mouse model. A Kmt5b gene-trap mouse line was obtained from the Knockout Mouse Project. Wild type (WT) and heterozygous (HET) mice were subjected to a comprehensive neurodevelopmental test battery to assess reflexes, motor behavior, learning/memory, social behavior, repetitive movement, and common ASD comorbidities (obsessive compulsion, depression, and anxiety). Given the strong sex bias observed in the ASD patient population, we tested both a male and female cohort of animals and compared differences between genotypes and sexes. HET mice were significantly smaller than WT littermates starting at postnatal day 10 through young adulthood which was correlated with smaller brain size (i.e., microcephaly). This was more severe in males than females. HET male neonates also had delayed eye opening and significantly weaker reflexes than WT littermates. In young adults, significant differences between genotypes relative to anxiety, depression, fear, and extinction learning were observed. Interestingly, several sexually dimorphic differences were noted including increased repetitive grooming behavior in HET females and an increased latency to hot plate response in HET females versus a decreased latency in HET males. LAY SUMMARY: Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet its role in the brain is not known. Our study indicates that mice lacking one genomic copy of Kmt5b show deficits in neonatal reflexes, sociability, repetitive stress-induced grooming, changes in thermal pain sensing, decreased depression and anxiety, increased fear, slower extinction learning, and lower body weight, length, and brain size. Furthermore, several outcomes differed by sex, perhaps mirroring the sex bias in ASD. En ligne : http://dx.doi.org/10.1002/aur.2516 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449
in Autism Research > 14-8 (August 2021) . - p.1554-1571[article] Differential effects by sex with Kmt5b loss [Texte imprimé et/ou numérique] / R. N. WICKRAMASEKARA, Auteur ; B. ROBERTSON, Auteur ; J. HULEN, Auteur ; J. HALLGREN, Auteur ; H. A. F. STESSMAN, Auteur . - p.1554-1571.
Langues : Anglais (eng)
in Autism Research > 14-8 (August 2021) . - p.1554-1571
Mots-clés : Adult Animals Anxiety/genetics Autism Spectrum Disorder/genetics Disease Models, Animal Fear Female Grooming Humans Male Mice Mice, Knockout Social Behavior Young Adult genetics genotype-phenotype correlation mouse models Index. décimale : PER Périodiques Résumé : Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in genetic studies of neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet, its role in the brain is not known. The goal of this work was to neurodevelopmentally characterize the effect(s) of KMT5B haploinsufficiency using a mouse model. A Kmt5b gene-trap mouse line was obtained from the Knockout Mouse Project. Wild type (WT) and heterozygous (HET) mice were subjected to a comprehensive neurodevelopmental test battery to assess reflexes, motor behavior, learning/memory, social behavior, repetitive movement, and common ASD comorbidities (obsessive compulsion, depression, and anxiety). Given the strong sex bias observed in the ASD patient population, we tested both a male and female cohort of animals and compared differences between genotypes and sexes. HET mice were significantly smaller than WT littermates starting at postnatal day 10 through young adulthood which was correlated with smaller brain size (i.e., microcephaly). This was more severe in males than females. HET male neonates also had delayed eye opening and significantly weaker reflexes than WT littermates. In young adults, significant differences between genotypes relative to anxiety, depression, fear, and extinction learning were observed. Interestingly, several sexually dimorphic differences were noted including increased repetitive grooming behavior in HET females and an increased latency to hot plate response in HET females versus a decreased latency in HET males. LAY SUMMARY: Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet its role in the brain is not known. Our study indicates that mice lacking one genomic copy of Kmt5b show deficits in neonatal reflexes, sociability, repetitive stress-induced grooming, changes in thermal pain sensing, decreased depression and anxiety, increased fear, slower extinction learning, and lower body weight, length, and brain size. Furthermore, several outcomes differed by sex, perhaps mirroring the sex bias in ASD. En ligne : http://dx.doi.org/10.1002/aur.2516 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=449