31 recherche sur le mot-clé 'Disease Models, Animal'

Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder / Carol L. MURRAY ; John KEALY ; Clodagh TOWNS ; Andrew ROCHE ; Arshed NAZMI ; Michelle DORAN ; John P. LOWRY ; Colm CUNNINGHAM in Molecular Autism, 14 (2023)  

Public ISBD [article]  inMolecular Autism > 14 (2023) . - 43 p. Titre : Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Carol L. MURRAY, Auteur ; John KEALY, Auteur ; Clodagh TOWNS, Auteur ; Andrew ROCHE, Auteur ; Arshed NAZMI, Auteur ; Michelle DORAN, Auteur ; John P. LOWRY, Auteur ; Colm CUNNINGHAM, Auteur Article en page(s) : 43 p. Langues : Anglais (eng) Mots-clés : Humans  Mice  Animals  *Autism Spectrum Disorder/therapy  Lipopolysaccharides/toxicity  Temperature  Disease Models, Animal  Mice, Inbred Strains  Brain  *Hyperthermia, Induced/methods Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are predominantly neurodevelopmental and largely genetically determined. However, there are human data supporting the idea that fever can improve symptoms in some individuals, but those data are limited and there are almost no data to support this from animal models. We aimed to test the hypothesis that elevated body temperature would improve function in two animal models of ASD. METHODS: We used a 4 h whole-body hyperthermia (WBH) protocol and, separately, systemic inflammation induced by bacterial endotoxin (LPS) at 250 ug/kg, to dissociate temperature and inflammatory elements of fever in two ASD animal models: C58/J and Shank3B- mice. We used one- or two-way ANOVA and t-tests with normally distributed data and Kruskal-Wallis or Mann-Whitney with nonparametric data. Post hoc comparisons were made with a level of significance set at p<0.05. For correlation analyses, data were adjusted by a linear regression model. RESULTS: Only LPS induced inflammatory signatures in the brain while only WBH produced fever-range hyperthermia. WBH reduced repetitive behaviours and improved social interaction in C58/J mice and significantly reduced compulsive grooming in Shank3B- mice. LPS significantly suppressed most activities over 5-48 h. LIMITATIONS: We show behavioural, cellular and molecular changes, but provide no specific mechanistic explanation for the observed behavioural improvements. CONCLUSIONS: The data are the first, to our knowledge, to demonstrate that elevated body temperature can improve behavioural signs in 2 distinct ASD models. Given the developmental nature of ASD, evidence that symptoms may be improved by environmental perturbations indicates possibilities for improving function in these individuals. Since experimental hyperthermia in patients would carry significant risks, it is now essential to pursue molecular mechanisms through which hyperthermia might bring about the observed benefits. En ligne : https://dx.doi.org/10.1186/s13229-023-00569-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=518 [article] Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder [Texte imprimé et/ou numérique] / Carol L. MURRAY, Auteur ; John KEALY, Auteur ; Clodagh TOWNS, Auteur ; Andrew ROCHE, Auteur ; Arshed NAZMI, Auteur ; Michelle DORAN, Auteur ; John P. LOWRY, Auteur ; Colm CUNNINGHAM, Auteur . - 43 p. Langues : Anglais (eng) in Molecular Autism > 14 (2023) . - 43 p. Mots-clés : Humans  Mice  Animals  *Autism Spectrum Disorder/therapy  Lipopolysaccharides/toxicity  Temperature  Disease Models, Animal  Mice, Inbred Strains  Brain  *Hyperthermia, Induced/methods Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are predominantly neurodevelopmental and largely genetically determined. However, there are human data supporting the idea that fever can improve symptoms in some individuals, but those data are limited and there are almost no data to support this from animal models. We aimed to test the hypothesis that elevated body temperature would improve function in two animal models of ASD. METHODS: We used a 4 h whole-body hyperthermia (WBH) protocol and, separately, systemic inflammation induced by bacterial endotoxin (LPS) at 250 ug/kg, to dissociate temperature and inflammatory elements of fever in two ASD animal models: C58/J and Shank3B- mice. We used one- or two-way ANOVA and t-tests with normally distributed data and Kruskal-Wallis or Mann-Whitney with nonparametric data. Post hoc comparisons were made with a level of significance set at p<0.05. For correlation analyses, data were adjusted by a linear regression model. RESULTS: Only LPS induced inflammatory signatures in the brain while only WBH produced fever-range hyperthermia. WBH reduced repetitive behaviours and improved social interaction in C58/J mice and significantly reduced compulsive grooming in Shank3B- mice. LPS significantly suppressed most activities over 5-48 h. LIMITATIONS: We show behavioural, cellular and molecular changes, but provide no specific mechanistic explanation for the observed behavioural improvements. CONCLUSIONS: The data are the first, to our knowledge, to demonstrate that elevated body temperature can improve behavioural signs in 2 distinct ASD models. Given the developmental nature of ASD, evidence that symptoms may be improved by environmental perturbations indicates possibilities for improving function in these individuals. Since experimental hyperthermia in patients would carry significant risks, it is now essential to pursue molecular mechanisms through which hyperthermia might bring about the observed benefits. En ligne : https://dx.doi.org/10.1186/s13229-023-00569-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=518

Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder / Mohammed Sarfaraz NAWAZ ; Peter C KIND ; Michael A COUSIN in Molecular Autism, 16 (2025)  

Public ISBD [article]  inMolecular Autism > 16 (2025) . - 26 Titre : Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Mohammed Sarfaraz NAWAZ, Auteur ; Peter C KIND, Auteur ; Michael A COUSIN, Auteur Article en page(s) : 26 Langues : Anglais (eng) Mots-clés : Animals  Endocytosis  Disease Models, Animal  Rats  Synaptic Vesicles/metabolism  Autism Spectrum Disorder/metabolism/physiopathology/genetics/pathology  Neurons/metabolism  Cells, Cultured  Exocytosis  Activity  Autism  Endocytosis  Hippocampus  Presynapse  Rat  Vesicle  performed in accordance with the UK Animal (Scientific Procedures) Act 1986,  under Project and Personal Licence authority and were approved by the Animal  Welfare and Ethical Review Body at the University of Edinburgh (Home Office  project licence - 7008878). Similarly, procedures were conducted in accordance  with protocols approved by the Institutional Animal Ethics Committee of Institute  for Stem Cell Science and Regenerative Medicine, Bangalore. Consent for  publication: Not applicable. Competing interests: Peter Kind is an Associate  Editor for Molecular Autism. Index. décimale : PER Périodiques Résumé : BACKGROUND: The key pathological mechanisms underlying autism spectrum disorder (ASD) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders; however, it is unclear whether this dysfunction drives ASD or is an adaptation to the altered brain microenvironment. METHODS: To differentiate between these two competing scenarios, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in primary neuronal cultures derived from a series of preclinical rat models of monogenic ASD. These five independent models (Nrxn1(+/-), Nlgn3(-/y), Syngap(+/-), Syngap(+/?-GAP), Pten(+/-)) were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. Synaptic vesicle exocytosis and cargo trafficking were triggered via two discrete trains of activity and monitored using the genetically-encoded reporter synaptophysin-pHluorin. Activity-dependent bulk endocytosis was assessed during intense neuronal activity using the fluid phase marker tetramethylrhodamine-dextran. RESULTS: Both synaptic vesicle fusion events and cargo trafficking were unaffected in all models investigated under all stimulation protocols. However, a key convergent phenotype across neurons derived from all five models was revealed, a depression in activity-dependent bulk endocytosis. LIMITATIONS: The study is exclusively conducted in primary cultures of hippocampal neurons; therefore, the impact on neurons from other brain regions or altered brain microcircuitry was not assessed. No molecular mechanism has been identified for this depression. CONCLUSION: This suggests that depression of activity-dependent bulk endocytosis is a presynaptic homeostatic mechanism to correct for intrinsic dysfunction in ASD neurons. En ligne : https://dx.doi.org/10.1186/s13229-025-00660-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555 [article] Convergent depression of activity-dependent bulk endocytosis in rodent models of autism spectrum disorder [Texte imprimé et/ou numérique] / Mohammed Sarfaraz NAWAZ, Auteur ; Peter C KIND, Auteur ; Michael A COUSIN, Auteur . - 26. Langues : Anglais (eng) in Molecular Autism > 16 (2025) . - 26 Mots-clés : Animals  Endocytosis  Disease Models, Animal  Rats  Synaptic Vesicles/metabolism  Autism Spectrum Disorder/metabolism/physiopathology/genetics/pathology  Neurons/metabolism  Cells, Cultured  Exocytosis  Activity  Autism  Endocytosis  Hippocampus  Presynapse  Rat  Vesicle  performed in accordance with the UK Animal (Scientific Procedures) Act 1986,  under Project and Personal Licence authority and were approved by the Animal  Welfare and Ethical Review Body at the University of Edinburgh (Home Office  project licence - 7008878). Similarly, procedures were conducted in accordance  with protocols approved by the Institutional Animal Ethics Committee of Institute  for Stem Cell Science and Regenerative Medicine, Bangalore. Consent for  publication: Not applicable. Competing interests: Peter Kind is an Associate  Editor for Molecular Autism. Index. décimale : PER Périodiques Résumé : BACKGROUND: The key pathological mechanisms underlying autism spectrum disorder (ASD) remain relatively undetermined, potentially due to the heterogenous nature of the condition. Targeted studies of a series of monogenic ASDs have revealed postsynaptic dysfunction as a central conserved mechanism. Presynaptic dysfunction is emerging as an additional disease locus in neurodevelopmental disorders; however, it is unclear whether this dysfunction drives ASD or is an adaptation to the altered brain microenvironment. METHODS: To differentiate between these two competing scenarios, we performed a high content analysis of key stages of the synaptic vesicle lifecycle in primary neuronal cultures derived from a series of preclinical rat models of monogenic ASD. These five independent models (Nrxn1(+/-), Nlgn3(-/y), Syngap(+/-), Syngap(+/?-GAP), Pten(+/-)) were specifically selected to have perturbations in a diverse palette of genes that were expressed either at the pre- or post-synapse. Synaptic vesicle exocytosis and cargo trafficking were triggered via two discrete trains of activity and monitored using the genetically-encoded reporter synaptophysin-pHluorin. Activity-dependent bulk endocytosis was assessed during intense neuronal activity using the fluid phase marker tetramethylrhodamine-dextran. RESULTS: Both synaptic vesicle fusion events and cargo trafficking were unaffected in all models investigated under all stimulation protocols. However, a key convergent phenotype across neurons derived from all five models was revealed, a depression in activity-dependent bulk endocytosis. LIMITATIONS: The study is exclusively conducted in primary cultures of hippocampal neurons; therefore, the impact on neurons from other brain regions or altered brain microcircuitry was not assessed. No molecular mechanism has been identified for this depression. CONCLUSION: This suggests that depression of activity-dependent bulk endocytosis is a presynaptic homeostatic mechanism to correct for intrinsic dysfunction in ASD neurons. En ligne : https://dx.doi.org/10.1186/s13229-025-00660-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=555

Deep phenotyping reveals movement phenotypes in mouse neurodevelopmental models / Ugne KLIBAITE in Molecular Autism, 13 (2022)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 12 p. Titre : Deep phenotyping reveals movement phenotypes in mouse neurodevelopmental models Type de document : Texte imprimé et/ou numérique Auteurs : Ugne KLIBAITE, Auteur ; Mikhail KISLIN, Auteur ; Jessica L. VERPEUT, Auteur ; Silke BERGELER, Auteur ; Xiaoting SUN, Auteur ; Joshua W. SHAEVITZ, Auteur ; Samuel S.-H. WANG, Auteur Article en page(s) : 12 p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics  Disease Models, Animal  Female  Male  Membrane Proteins/genetics  Mice  Mice, Inbred C57BL  Mice, Knockout  Nerve Tissue Proteins/genetics  Phenotype  Tuberous Sclerosis Complex 1 Protein/genetics  Autism  Behavior  Cerebellum  Clustering  Mouse  Pose estimation Index. décimale : PER Périodiques Résumé : BACKGROUND: Repetitive action, resistance to environmental change and fine motor disruptions are hallmarks of autism spectrum disorder (ASD) and other neurodevelopmental disorders, and vary considerably from individual to individual. In animal models, conventional behavioral phenotyping captures such fine-scale variations incompletely. Here we observed male and female C57BL/6J mice to methodically catalog adaptive movement over multiple days and examined two rodent models of developmental disorders against this dynamic baseline. We then investigated the behavioral consequences of a cerebellum-specific deletion in Tsc1 protein and a whole-brain knockout in Cntnap2 protein in mice. Both of these mutations are found in clinical conditions and have been associated with ASD. METHODS: We used advances in computer vision and deep learning, namely a generalized form of high-dimensional statistical analysis, to develop a framework for characterizing mouse movement on multiple timescales using a single popular behavioral assay, the open-field test. The pipeline takes virtual markers from pose estimation to find behavior clusters and generate wavelet signatures of behavior classes. We measured spatial and temporal habituation to a new environment across minutes and days, different types of self-grooming, locomotion and gait. RESULTS: Both Cntnap2 knockouts and L7-Tsc1 mutants showed forelimb lag during gait. L7-Tsc1 mutants and Cntnap2 knockouts showed complex defects in multi-day adaptation, lacking the tendency of wild-type mice to spend progressively more time in corners of the arena. In L7-Tsc1 mutant mice, failure to adapt took the form of maintained ambling, turning and locomotion, and an overall decrease in grooming. However, adaptation in these traits was similar between wild-type mice and Cntnap2 knockouts. L7-Tsc1 mutant and Cntnap2 knockout mouse models showed different patterns of behavioral state occupancy. LIMITATIONS: Genetic risk factors for autism are numerous, and we tested only two. Our pipeline was only done under conditions of free behavior. Testing under task or social conditions would reveal more information about behavioral dynamics and variability. CONCLUSIONS: Our automated pipeline for deep phenotyping successfully captures model-specific deviations in adaptation and movement as well as differences in the detailed structure of behavioral dynamics. The reported deficits indicate that deep phenotyping constitutes a robust set of ASD symptoms that may be considered for implementation in clinical settings as quantitative diagnosis criteria. En ligne : http://dx.doi.org/10.1186/s13229-022-00492-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477 [article] Deep phenotyping reveals movement phenotypes in mouse neurodevelopmental models [Texte imprimé et/ou numérique] / Ugne KLIBAITE, Auteur ; Mikhail KISLIN, Auteur ; Jessica L. VERPEUT, Auteur ; Silke BERGELER, Auteur ; Xiaoting SUN, Auteur ; Joshua W. SHAEVITZ, Auteur ; Samuel S.-H. WANG, Auteur . - 12 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 12 p. Mots-clés : Animals  Autism Spectrum Disorder/genetics  Disease Models, Animal  Female  Male  Membrane Proteins/genetics  Mice  Mice, Inbred C57BL  Mice, Knockout  Nerve Tissue Proteins/genetics  Phenotype  Tuberous Sclerosis Complex 1 Protein/genetics  Autism  Behavior  Cerebellum  Clustering  Mouse  Pose estimation Index. décimale : PER Périodiques Résumé : BACKGROUND: Repetitive action, resistance to environmental change and fine motor disruptions are hallmarks of autism spectrum disorder (ASD) and other neurodevelopmental disorders, and vary considerably from individual to individual. In animal models, conventional behavioral phenotyping captures such fine-scale variations incompletely. Here we observed male and female C57BL/6J mice to methodically catalog adaptive movement over multiple days and examined two rodent models of developmental disorders against this dynamic baseline. We then investigated the behavioral consequences of a cerebellum-specific deletion in Tsc1 protein and a whole-brain knockout in Cntnap2 protein in mice. Both of these mutations are found in clinical conditions and have been associated with ASD. METHODS: We used advances in computer vision and deep learning, namely a generalized form of high-dimensional statistical analysis, to develop a framework for characterizing mouse movement on multiple timescales using a single popular behavioral assay, the open-field test. The pipeline takes virtual markers from pose estimation to find behavior clusters and generate wavelet signatures of behavior classes. We measured spatial and temporal habituation to a new environment across minutes and days, different types of self-grooming, locomotion and gait. RESULTS: Both Cntnap2 knockouts and L7-Tsc1 mutants showed forelimb lag during gait. L7-Tsc1 mutants and Cntnap2 knockouts showed complex defects in multi-day adaptation, lacking the tendency of wild-type mice to spend progressively more time in corners of the arena. In L7-Tsc1 mutant mice, failure to adapt took the form of maintained ambling, turning and locomotion, and an overall decrease in grooming. However, adaptation in these traits was similar between wild-type mice and Cntnap2 knockouts. L7-Tsc1 mutant and Cntnap2 knockout mouse models showed different patterns of behavioral state occupancy. LIMITATIONS: Genetic risk factors for autism are numerous, and we tested only two. Our pipeline was only done under conditions of free behavior. Testing under task or social conditions would reveal more information about behavioral dynamics and variability. CONCLUSIONS: Our automated pipeline for deep phenotyping successfully captures model-specific deviations in adaptation and movement as well as differences in the detailed structure of behavioral dynamics. The reported deficits indicate that deep phenotyping constitutes a robust set of ASD symptoms that may be considered for implementation in clinical settings as quantitative diagnosis criteria. En ligne : http://dx.doi.org/10.1186/s13229-022-00492-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=477

Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs / Feipeng ZHU in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 9p. Titre : Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs Type de document : Texte imprimé et/ou numérique Auteurs : Feipeng ZHU, Auteur ; Qi SHI, Auteur ; Yong-hui JIANG, Auteur ; Yong Q. ZHANG, Auteur ; Hui ZHAO, Auteur Article en page(s) : 9p. Langues : Anglais (eng) Mots-clés : Humans  Dogs  Animals  Autistic Disorder/genetics  Autism Spectrum Disorder  Nerve Tissue Proteins/genetics/metabolism  Pyramidal Cells/metabolism  Synaptic Transmission/genetics  Prefrontal Cortex  Anxiety  Disease Models, Animal  Autism spectrum disorder  Dog  Excitability  Shank3  Synaptic transmission Index. décimale : PER Périodiques Résumé : BACKGROUND: SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified. METHODS: We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy. RESULTS: We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability. LIMITATIONS: Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors. CONCLUSIONS: Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research. En ligne : https://dx.doi.org/10.1186/s13229-024-00587-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs [Texte imprimé et/ou numérique] / Feipeng ZHU, Auteur ; Qi SHI, Auteur ; Yong-hui JIANG, Auteur ; Yong Q. ZHANG, Auteur ; Hui ZHAO, Auteur . - 9p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 9p. Mots-clés : Humans  Dogs  Animals  Autistic Disorder/genetics  Autism Spectrum Disorder  Nerve Tissue Proteins/genetics/metabolism  Pyramidal Cells/metabolism  Synaptic Transmission/genetics  Prefrontal Cortex  Anxiety  Disease Models, Animal  Autism spectrum disorder  Dog  Excitability  Shank3  Synaptic transmission Index. décimale : PER Périodiques Résumé : BACKGROUND: SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified. METHODS: We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy. RESULTS: We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability. LIMITATIONS: Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors. CONCLUSIONS: Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research. En ligne : https://dx.doi.org/10.1186/s13229-024-00587-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism-like social impairment / A. BANERJEE in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 16p. Titre : Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism-like social impairment Type de document : Texte imprimé et/ou numérique Auteurs : A. BANERJEE, Auteur ; J. A. LUONG, Auteur ; A. HO, Auteur ; A. O. SAIB, Auteur ; J. E. PLOSKI, Auteur Article en page(s) : 16p. Langues : Anglais (eng) Mots-clés : Acoustic Stimulation  Animals  Autism Spectrum Disorder/etiology  Basolateral Nuclear Complex/drug effects/metabolism  Carrier Proteins/biosynthesis/genetics/physiology  Conditioning, Classical/physiology  Disease Models, Animal  Electroshock  Exploratory Behavior/drug effects/physiology  Fear/drug effects/physiology  Female  Freezing Reaction, Cataleptic  Gene Expression Regulation/drug effects  Genetic Vectors/administration & dosage/genetics  Homer Scaffolding Proteins  Nerve Tissue Proteins/biosynthesis/genetics/physiology  Pregnancy  Prenatal Exposure Delayed Effects  RNA, Messenger/biosynthesis  Rats  Recombinant Fusion Proteins/biosynthesis/genetics  Social Behavior  Teratogens/pharmacology  Transduction, Genetic  Valproic Acid/pharmacology  Amygdala  Autism  Emotion  Homer1a  Learning  Memory  Pavlovian fear conditioning  Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASDs) represent a heterogeneous group of disorders with a wide range of behavioral impairments including social and communication deficits. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety, and some studies indicate that a subset of ASD individuals have a reduced ability to be fear conditioned. Deciphering the molecular basis of ASD has been considerably challenging and it currently remains poorly understood. In this study we examined the molecular basis of autism-like impairments in an environmentally induced animal model of ASD, where pregnant rats are exposed to the known teratogen, valproic acid (VPA), on day 12.5 of gestation and the subsequent progeny exhibit ASD-like symptoms. We focused our analysis on the basal and lateral nucleus of the amygdala (BLA), a region of the brain found to be associated with ASD pathology. METHODS: We performed whole genome gene expression analysis on the BLA using DNA microarrays to examine differences in gene expression within the amygdala of VPA-exposed animals. We validated one VPA-dysregulated candidate gene (Homer1a) using both quantitative PCR (qRT-PCR) and western blot. Finally, we overexpressed Homer1a within the basal and lateral amygdala of naive animals utilizing adeno-associated viruses (AAV) and subsequently examined these animals in a battery of behavioral tests associated with ASD, including auditory fear conditioning, social interaction and open field. RESULTS: Our microarray data indicated that Homer1a was one of the genes which exhibited a significant upregulation within the amygdala. We observed an increase in Homer1a messenger RNA (mRNA) and protein in multiple cohorts of VPA-exposed animals indicating that dysregulation of Homer1a levels might underlie some of the symptoms exhibited by VPA-exposed animals. To test this hypothesis, we overexpressed Homer1a within BLA neurons utilizing a viral-mediated approach and found that overexpression of Homer1a impaired auditory fear conditioning and reduced social interaction, while having no influence on open-field behavior. CONCLUSIONS: This study indicates that dysregulation of amygdala Homer1a might contribute to some autism-like symptoms induced by VPA exposure. These findings are interesting in part because Homer1a influences the functioning of Shank3, metabotropic glutamate receptors (mGluR5), and Homer1, and these proteins have previously been associated with ASD, indicating that these differing models of ASD may have a similar molecular basis. En ligne : http://dx.doi.org/10.1186/s13229-016-0077-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328 [article] Overexpression of Homer1a in the basal and lateral amygdala impairs fear conditioning and induces an autism-like social impairment [Texte imprimé et/ou numérique] / A. BANERJEE, Auteur ; J. A. LUONG, Auteur ; A. HO, Auteur ; A. O. SAIB, Auteur ; J. E. PLOSKI, Auteur . - 16p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 16p. Mots-clés : Acoustic Stimulation  Animals  Autism Spectrum Disorder/etiology  Basolateral Nuclear Complex/drug effects/metabolism  Carrier Proteins/biosynthesis/genetics/physiology  Conditioning, Classical/physiology  Disease Models, Animal  Electroshock  Exploratory Behavior/drug effects/physiology  Fear/drug effects/physiology  Female  Freezing Reaction, Cataleptic  Gene Expression Regulation/drug effects  Genetic Vectors/administration & dosage/genetics  Homer Scaffolding Proteins  Nerve Tissue Proteins/biosynthesis/genetics/physiology  Pregnancy  Prenatal Exposure Delayed Effects  RNA, Messenger/biosynthesis  Rats  Recombinant Fusion Proteins/biosynthesis/genetics  Social Behavior  Teratogens/pharmacology  Transduction, Genetic  Valproic Acid/pharmacology  Amygdala  Autism  Emotion  Homer1a  Learning  Memory  Pavlovian fear conditioning  Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASDs) represent a heterogeneous group of disorders with a wide range of behavioral impairments including social and communication deficits. Apart from these core symptoms, a significant number of ASD individuals display higher levels of anxiety, and some studies indicate that a subset of ASD individuals have a reduced ability to be fear conditioned. Deciphering the molecular basis of ASD has been considerably challenging and it currently remains poorly understood. In this study we examined the molecular basis of autism-like impairments in an environmentally induced animal model of ASD, where pregnant rats are exposed to the known teratogen, valproic acid (VPA), on day 12.5 of gestation and the subsequent progeny exhibit ASD-like symptoms. We focused our analysis on the basal and lateral nucleus of the amygdala (BLA), a region of the brain found to be associated with ASD pathology. METHODS: We performed whole genome gene expression analysis on the BLA using DNA microarrays to examine differences in gene expression within the amygdala of VPA-exposed animals. We validated one VPA-dysregulated candidate gene (Homer1a) using both quantitative PCR (qRT-PCR) and western blot. Finally, we overexpressed Homer1a within the basal and lateral amygdala of naive animals utilizing adeno-associated viruses (AAV) and subsequently examined these animals in a battery of behavioral tests associated with ASD, including auditory fear conditioning, social interaction and open field. RESULTS: Our microarray data indicated that Homer1a was one of the genes which exhibited a significant upregulation within the amygdala. We observed an increase in Homer1a messenger RNA (mRNA) and protein in multiple cohorts of VPA-exposed animals indicating that dysregulation of Homer1a levels might underlie some of the symptoms exhibited by VPA-exposed animals. To test this hypothesis, we overexpressed Homer1a within BLA neurons utilizing a viral-mediated approach and found that overexpression of Homer1a impaired auditory fear conditioning and reduced social interaction, while having no influence on open-field behavior. CONCLUSIONS: This study indicates that dysregulation of amygdala Homer1a might contribute to some autism-like symptoms induced by VPA exposure. These findings are interesting in part because Homer1a influences the functioning of Shank3, metabotropic glutamate receptors (mGluR5), and Homer1, and these proteins have previously been associated with ASD, indicating that these differing models of ASD may have a similar molecular basis. En ligne : http://dx.doi.org/10.1186/s13229-016-0077-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328

The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism / F. LIU in Molecular Autism, 9 (2018)  

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Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome / Magdalena KALINOWSKA in Molecular Autism, 13 (2022)  

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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)  

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

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Enhanced fear limits behavioral flexibility in Shank2-deficient mice / Miru YUN in Molecular Autism, 13 (2022)  

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