24 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

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

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)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 61 p. Titre : The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism Type de document : Texte imprimé et/ou numérique Auteurs : F. LIU, Auteur ; K. HORTON-SPARKS, Auteur ; V. HULL, Auteur ; R. W. LI, Auteur ; V. MARTINEZ-CERDENO, Auteur Article en page(s) : 61 p. Langues : Anglais (eng) Mots-clés : Animals  Autistic Disorder/etiology/*microbiology  Bacterial Typing Techniques  Disease Models, Animal  Dysbiosis/etiology/*microbiology  *Gastrointestinal Microbiome  Rats  Rats, Sprague-Dawley  Valproic Acid/administration & dosage/toxicity Index. décimale : PER Périodiques Résumé : Background: Gut microbiota has the capacity to impact the regular function of the brain, which can in turn affect the composition of microbiota. Autism spectrum disorder (ASD) patients suffer from gastrointestinal problems and experience changes in gut microbiota; however, it is not yet clear whether the change in the microbiota associated with ASD is a cause or a consequence of the disease. Methods: We have investigated the species richness and microbial composition in a valproic acid (VPA)-induced rat model autism. Fecal samples from the rectum were collected at necropsy, microbial total DNA was extracted, 16 rRNA genes sequenced using Illumina, and the global microbial co-occurrence network was constructed using a random matrix theory-based pipeline. Collected rat microbiome data were compared to available data derived from cases of autism. Results: We found that VPA administration during pregnancy reduced fecal microbial richness, changed the gut microbial composition, and altered the metabolite potential of the fecal microbial community in a pattern similar to that seen in patients with ASD. However, the global network property and network composition as well as microbial co-occurrence patterns were largely preserved in the offspring of rats exposed to prenatal administration of VPA. Conclusions: Our data on the microbiota of the VPA rat model of autism indicate that this model, in addition to behaviorally and anatomically mimicking the autistic brain as previously shown, also mimics the microbiome features of autism, making it one of the best-suited rodent models for the study of autism and ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0251-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism [Texte imprimé et/ou numérique] / F. LIU, Auteur ; K. HORTON-SPARKS, Auteur ; V. HULL, Auteur ; R. W. LI, Auteur ; V. MARTINEZ-CERDENO, Auteur . - 61 p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 61 p. Mots-clés : Animals  Autistic Disorder/etiology/*microbiology  Bacterial Typing Techniques  Disease Models, Animal  Dysbiosis/etiology/*microbiology  *Gastrointestinal Microbiome  Rats  Rats, Sprague-Dawley  Valproic Acid/administration & dosage/toxicity Index. décimale : PER Périodiques Résumé : Background: Gut microbiota has the capacity to impact the regular function of the brain, which can in turn affect the composition of microbiota. Autism spectrum disorder (ASD) patients suffer from gastrointestinal problems and experience changes in gut microbiota; however, it is not yet clear whether the change in the microbiota associated with ASD is a cause or a consequence of the disease. Methods: We have investigated the species richness and microbial composition in a valproic acid (VPA)-induced rat model autism. Fecal samples from the rectum were collected at necropsy, microbial total DNA was extracted, 16 rRNA genes sequenced using Illumina, and the global microbial co-occurrence network was constructed using a random matrix theory-based pipeline. Collected rat microbiome data were compared to available data derived from cases of autism. Results: We found that VPA administration during pregnancy reduced fecal microbial richness, changed the gut microbial composition, and altered the metabolite potential of the fecal microbial community in a pattern similar to that seen in patients with ASD. However, the global network property and network composition as well as microbial co-occurrence patterns were largely preserved in the offspring of rats exposed to prenatal administration of VPA. Conclusions: Our data on the microbiota of the VPA rat model of autism indicate that this model, in addition to behaviorally and anatomically mimicking the autistic brain as previously shown, also mimics the microbiome features of autism, making it one of the best-suited rodent models for the study of autism and ASD. En ligne : https://dx.doi.org/10.1186/s13229-018-0251-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

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)  

Public ISBD [article]  inMolecular Autism > 13 (2022) . - 29 p. Titre : Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Magdalena KALINOWSKA, Auteur ; Mathijs B. VAN DER LEI, Auteur ; Michael KITIASHVILI, Auteur ; Maggie MAMCARZ, Auteur ; Mauricio M. OLIVEIRA, Auteur ; Francesco LONGO, Auteur ; Eric KLANN, Auteur Article en page(s) : 29 p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/metabolism  Disease Models, Animal  Fragile X Mental Retardation Protein/genetics/metabolism  Fragile X Syndrome/genetics/metabolism/pathology  Mice  Mice, Knockout  Neurons/metabolism/pathology  Parvalbumins/metabolism  RNA, Messenger/metabolism  Somatostatin/metabolism  Autism  Behavior  Fmrp  Fragile X syndrome  Inhibitory neurons  Protein synthesis Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes. The role of FMRP in morphology and function of excitatory neurons has been well studied in mice lacking Fmr1, but the impact of Fmr1 deletion on inhibitory neurons remains less characterized. Moreover, the contribution of FMRP in different cell types to FXS pathophysiology is not well defined. We sought to characterize whether FMRP loss in parvalbumin or somatostatin-expressing neurons results in FXS-like deficits in mice. METHODS: We used Cre-lox recombinase technology to generate two lines of conditional knockout mice lacking FMRP in either parvalbumin or somatostatin-expressing cells and carried out a battery of behavioral tests to assess motor function, anxiety, repetitive, stereotypic, social behaviors, and learning and memory. In addition, we used fluorescent non-canonical amino acid tagging along with immunostaining to determine whether de novo protein synthesis is dysregulated in parvalbumin or somatostatin-expressing neurons. RESULTS: De novo protein synthesis was elevated in hippocampal parvalbumin and somatostatin-expressing inhibitory neurons in Fmr1 knockout mice. Cell type-specific deletion of Fmr1 in parvalbumin-expressing neurons resulted in anxiety-like behavior, impaired social behavior, and dysregulated de novo protein synthesis. In contrast, deletion of Fmr1 in somatostatin-expressing neurons did not result in behavioral abnormalities and did not significantly impact de novo protein synthesis. This is the first report of how loss of FMRP in two specific subtypes of inhibitory neurons is associated with distinct FXS-like abnormalities. LIMITATIONS: The mouse models we generated are limited by whole body knockout of FMRP in parvalbumin or somatostatin-expressing cells and further studies are needed to establish a causal relationship between cellular deficits and FXS-like behaviors. CONCLUSIONS: Our findings indicate a cell type-specific role for FMRP in parvalbumin-expressing neurons in regulating distinct behavioral features associated with FXS. En ligne : http://dx.doi.org/10.1186/s13229-022-00509-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491 [article] Deletion of Fmr1 in parvalbumin-expressing neurons results in dysregulated translation and selective behavioral deficits associated with fragile X syndrome [Texte imprimé et/ou numérique] / Magdalena KALINOWSKA, Auteur ; Mathijs B. VAN DER LEI, Auteur ; Michael KITIASHVILI, Auteur ; Maggie MAMCARZ, Auteur ; Mauricio M. OLIVEIRA, Auteur ; Francesco LONGO, Auteur ; Eric KLANN, Auteur . - 29 p. Langues : Anglais (eng) in Molecular Autism > 13 (2022) . - 29 p. Mots-clés : Animals  Autism Spectrum Disorder/metabolism  Disease Models, Animal  Fragile X Mental Retardation Protein/genetics/metabolism  Fragile X Syndrome/genetics/metabolism/pathology  Mice  Mice, Knockout  Neurons/metabolism/pathology  Parvalbumins/metabolism  RNA, Messenger/metabolism  Somatostatin/metabolism  Autism  Behavior  Fmrp  Fragile X syndrome  Inhibitory neurons  Protein synthesis Index. décimale : PER Périodiques Résumé : BACKGROUND: Fragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes. The role of FMRP in morphology and function of excitatory neurons has been well studied in mice lacking Fmr1, but the impact of Fmr1 deletion on inhibitory neurons remains less characterized. Moreover, the contribution of FMRP in different cell types to FXS pathophysiology is not well defined. We sought to characterize whether FMRP loss in parvalbumin or somatostatin-expressing neurons results in FXS-like deficits in mice. METHODS: We used Cre-lox recombinase technology to generate two lines of conditional knockout mice lacking FMRP in either parvalbumin or somatostatin-expressing cells and carried out a battery of behavioral tests to assess motor function, anxiety, repetitive, stereotypic, social behaviors, and learning and memory. In addition, we used fluorescent non-canonical amino acid tagging along with immunostaining to determine whether de novo protein synthesis is dysregulated in parvalbumin or somatostatin-expressing neurons. RESULTS: De novo protein synthesis was elevated in hippocampal parvalbumin and somatostatin-expressing inhibitory neurons in Fmr1 knockout mice. Cell type-specific deletion of Fmr1 in parvalbumin-expressing neurons resulted in anxiety-like behavior, impaired social behavior, and dysregulated de novo protein synthesis. In contrast, deletion of Fmr1 in somatostatin-expressing neurons did not result in behavioral abnormalities and did not significantly impact de novo protein synthesis. This is the first report of how loss of FMRP in two specific subtypes of inhibitory neurons is associated with distinct FXS-like abnormalities. LIMITATIONS: The mouse models we generated are limited by whole body knockout of FMRP in parvalbumin or somatostatin-expressing cells and further studies are needed to establish a causal relationship between cellular deficits and FXS-like behaviors. CONCLUSIONS: Our findings indicate a cell type-specific role for FMRP in parvalbumin-expressing neurons in regulating distinct behavioral features associated with FXS. En ligne : http://dx.doi.org/10.1186/s13229-022-00509-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=491

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)  

Permalink

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

Permalink

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

Permalink

Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome / Antonis ASIMINAS in Molecular Autism, 13 (2022)  

Permalink

Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder / C. NEWELL in Molecular Autism, 7 (2016)  

Permalink