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Microglia in the Cerebral Cortex in Autism / Nicole A. TETREAULT in Journal of Autism and Developmental Disorders, 42-12 (December 2012)
[article]
Titre : Microglia in the Cerebral Cortex in Autism Type de document : Texte imprimé et/ou numérique Auteurs : Nicole A. TETREAULT, Auteur ; Atiya Y. HAKEEM, Auteur ; Sue JIANG, Auteur ; Brian A. WILLIAMS, Auteur ; Elizabeth ALLMAN, Auteur ; Barbara J. WOLD, Auteur ; John M. ALLMAN, Auteur Article en page(s) : p.2569-2584 Langues : Anglais (eng) Mots-clés : Microglia Autism Fronto-insular cortex Visual cortex Index. décimale : PER Périodiques Résumé : We immunocytochemically identified microglia in fronto-insular (FI) and visual cortex (VC) in autopsy brains of well-phenotyped subjects with autism and matched controls, and stereologically quantified the microglial densities. Densities were determined blind to phenotype using an optical fractionator probe. In FI, individuals with autism had significantly more microglia compared to controls (p = 0.02). One such subject had a microglial density in FI within the control range and was also an outlier behaviorally with respect to other subjects with autism. In VC, microglial densities were also significantly greater in individuals with autism versus controls (p = 0.0002). Since we observed increased densities of microglia in two functionally and anatomically disparate cortical areas, we suggest that these immune cells are probably denser throughout cerebral cortex in brains of people with autism. En ligne : http://dx.doi.org/10.1007/s10803-012-1513-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=184
in Journal of Autism and Developmental Disorders > 42-12 (December 2012) . - p.2569-2584[article] Microglia in the Cerebral Cortex in Autism [Texte imprimé et/ou numérique] / Nicole A. TETREAULT, Auteur ; Atiya Y. HAKEEM, Auteur ; Sue JIANG, Auteur ; Brian A. WILLIAMS, Auteur ; Elizabeth ALLMAN, Auteur ; Barbara J. WOLD, Auteur ; John M. ALLMAN, Auteur . - p.2569-2584.
Langues : Anglais (eng)
in Journal of Autism and Developmental Disorders > 42-12 (December 2012) . - p.2569-2584
Mots-clés : Microglia Autism Fronto-insular cortex Visual cortex Index. décimale : PER Périodiques Résumé : We immunocytochemically identified microglia in fronto-insular (FI) and visual cortex (VC) in autopsy brains of well-phenotyped subjects with autism and matched controls, and stereologically quantified the microglial densities. Densities were determined blind to phenotype using an optical fractionator probe. In FI, individuals with autism had significantly more microglia compared to controls (p = 0.02). One such subject had a microglial density in FI within the control range and was also an outlier behaviorally with respect to other subjects with autism. In VC, microglial densities were also significantly greater in individuals with autism versus controls (p = 0.0002). Since we observed increased densities of microglia in two functionally and anatomically disparate cortical areas, we suggest that these immune cells are probably denser throughout cerebral cortex in brains of people with autism. En ligne : http://dx.doi.org/10.1007/s10803-012-1513-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=184 Altered Peripheral and Central Inflammatory Responses in a Mouse Model of Autism / Luciana LUCCHINA in Autism Research, 7-2 (April 2014)
[article]
Titre : Altered Peripheral and Central Inflammatory Responses in a Mouse Model of Autism Type de document : Texte imprimé et/ou numérique Auteurs : Luciana LUCCHINA, Auteur ; Amaicha Mara DEPINO, Auteur Article en page(s) : p.273-289 Mots-clés : valproic acid cytokines microglia astroglia hypothalamus–pituitary–adrenal axis behavior Index. décimale : PER Périodiques Résumé : Increasing clinical and experimental evidence links immune and inflammatory alterations with the pathogenesis of autism spectrum disorders (ASD). Autistic individuals show signs of neuroinflammation, altered inflammatory responses, and immune abnormalities throughout life. Mice injected subcutaneously with 600?mg/kg valproic acid (VPA600) at gestational day 12.5 show reduced social interaction in adulthood (at 8 weeks of age), and they have been proposed as a mouse model of autism. Here, we show that these adult animals present signs of chronic glial activation in the hippocampus and the cerebellum. Moreover, when they are challenged with a peripheral inflammatory stimulus (intraperitoneal lipopolysaccharides, LPS), VPA600 animals show an exacerbated inflammatory response. Two hours after LPS injection, VPA600 animals secrete more corticosterone to the blood than control mice, and show an increase in the levels of expression of proinflammatory cytokines in the spleen. After LPS challenge, VPA600 mice also show signs of increased neuroinflammation compared with control mice: they have more microglial cells in the hippocampus, and they show higher levels of proinflammatory cytokines in the cerebellum. Our results provide evidence of basal neuroinflammation and an altered inflammatory response in the VPA model of autism. We propose that this model can be used to evaluate the contribution of inflammatory reactivity to autism-related behaviors. These studies will contribute to elucidate the role of the inflammatory alterations observed in ASD individuals. En ligne : http://dx.doi.org/10.1002/aur.1338 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=230
in Autism Research > 7-2 (April 2014) . - p.273-289[article] Altered Peripheral and Central Inflammatory Responses in a Mouse Model of Autism [Texte imprimé et/ou numérique] / Luciana LUCCHINA, Auteur ; Amaicha Mara DEPINO, Auteur . - p.273-289.
in Autism Research > 7-2 (April 2014) . - p.273-289
Mots-clés : valproic acid cytokines microglia astroglia hypothalamus–pituitary–adrenal axis behavior Index. décimale : PER Périodiques Résumé : Increasing clinical and experimental evidence links immune and inflammatory alterations with the pathogenesis of autism spectrum disorders (ASD). Autistic individuals show signs of neuroinflammation, altered inflammatory responses, and immune abnormalities throughout life. Mice injected subcutaneously with 600?mg/kg valproic acid (VPA600) at gestational day 12.5 show reduced social interaction in adulthood (at 8 weeks of age), and they have been proposed as a mouse model of autism. Here, we show that these adult animals present signs of chronic glial activation in the hippocampus and the cerebellum. Moreover, when they are challenged with a peripheral inflammatory stimulus (intraperitoneal lipopolysaccharides, LPS), VPA600 animals show an exacerbated inflammatory response. Two hours after LPS injection, VPA600 animals secrete more corticosterone to the blood than control mice, and show an increase in the levels of expression of proinflammatory cytokines in the spleen. After LPS challenge, VPA600 mice also show signs of increased neuroinflammation compared with control mice: they have more microglial cells in the hippocampus, and they show higher levels of proinflammatory cytokines in the cerebellum. Our results provide evidence of basal neuroinflammation and an altered inflammatory response in the VPA model of autism. We propose that this model can be used to evaluate the contribution of inflammatory reactivity to autism-related behaviors. These studies will contribute to elucidate the role of the inflammatory alterations observed in ASD individuals. En ligne : http://dx.doi.org/10.1002/aur.1338 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=230 Germline nuclear-predominant Pten murine model exhibits impaired social and perseverative behavior, microglial activation, and increased oxytocinergic activity / N. SARN in Molecular Autism, 12 (2021)
[article]
Titre : Germline nuclear-predominant Pten murine model exhibits impaired social and perseverative behavior, microglial activation, and increased oxytocinergic activity Type de document : Texte imprimé et/ou numérique Auteurs : N. SARN, Auteur ; S. THACKER, Auteur ; H. LEE, Auteur ; C. ENG, Auteur Article en page(s) : 41 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Complement Microglia Mouse model Neurodegeneration Neuroinflammation Oxytocin PTEN mutation Social impairment Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) has a strong genetic etiology. Germline mutation in the tumor suppressor gene PTEN is one of the best described monogenic risk cases for ASD. Animal modeling of cell-specific Pten loss or mutation has provided insight into how disruptions to the function of PTEN affect neurodevelopment, neurobiology, and social behavior. As such, there is a growing need to understand more about how various aspects of PTEN activity and cell-compartment-specific functions, contribute to certain neurological or behavior phenotypes. METHODS: To understand more about the relationship between Pten localization and downstream effects on neurophenotypes, we generated the nuclear-predominant Pten(Y68H/+) mouse, which is identical to the genotype of some PTEN-ASD individuals. We subjected the Pten(Y68H/+) mouse to morphological and behavioral phenotyping, including the three-chamber sociability, open field, rotarod, and marble burying tests. We subsequently performed in vivo and in vitro cellular phenotyping and concluded the work with a transcriptomic survey of the Pten(Y68H/+) cortex, which profiled gene expression. RESULTS: We observe a significant increase in P-Akt downstream of canonical Pten signaling, macrocephaly, decreased sociability, decreased preference for novel social stimuli, increased repetitive behavior, and increased thigmotaxis in Pten(Y68H/+) six-week-old (P40) mice. In addition, we found significant microglial activation with increased expression of complement and neuroinflammatory proteins in vivo and in vitro accompanied by enhanced phagocytosis. These observations were subsequently validated with RNA-seq and qRT-PCR, which revealed overexpression of many genes involved in neuroinflammation and neuronal function, including oxytocin. Oxytocin transcript was fivefold overexpressed (P?=?0.0018), and oxytocin protein was strongly overexpressed in the Pten(Y68H/+) hypothalamus. CONCLUSIONS: The nuclear-predominant Pten(Y68H/+) model has clarified that Pten dysfunction links to microglial pathology and this associates with increased Akt signaling. We also demonstrate that Pten dysfunction associates with changes in the oxytocin system, an important connection between a prominent ASD risk gene and a potent neuroendocrine regulator of social behavior. These cellular and molecular pathologies may related to the observed changes in social behavior. Ultimately, the findings from this work may reveal important biomarkers and/or novel therapeutic modalities that could be explored in individuals with germline mutations in PTEN with ASD. En ligne : http://dx.doi.org/10.1186/s13229-021-00448-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459
in Molecular Autism > 12 (2021) . - 41 p.[article] Germline nuclear-predominant Pten murine model exhibits impaired social and perseverative behavior, microglial activation, and increased oxytocinergic activity [Texte imprimé et/ou numérique] / N. SARN, Auteur ; S. THACKER, Auteur ; H. LEE, Auteur ; C. ENG, Auteur . - 41 p.
Langues : Anglais (eng)
in Molecular Autism > 12 (2021) . - 41 p.
Mots-clés : Autism spectrum disorder Complement Microglia Mouse model Neurodegeneration Neuroinflammation Oxytocin PTEN mutation Social impairment Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) has a strong genetic etiology. Germline mutation in the tumor suppressor gene PTEN is one of the best described monogenic risk cases for ASD. Animal modeling of cell-specific Pten loss or mutation has provided insight into how disruptions to the function of PTEN affect neurodevelopment, neurobiology, and social behavior. As such, there is a growing need to understand more about how various aspects of PTEN activity and cell-compartment-specific functions, contribute to certain neurological or behavior phenotypes. METHODS: To understand more about the relationship between Pten localization and downstream effects on neurophenotypes, we generated the nuclear-predominant Pten(Y68H/+) mouse, which is identical to the genotype of some PTEN-ASD individuals. We subjected the Pten(Y68H/+) mouse to morphological and behavioral phenotyping, including the three-chamber sociability, open field, rotarod, and marble burying tests. We subsequently performed in vivo and in vitro cellular phenotyping and concluded the work with a transcriptomic survey of the Pten(Y68H/+) cortex, which profiled gene expression. RESULTS: We observe a significant increase in P-Akt downstream of canonical Pten signaling, macrocephaly, decreased sociability, decreased preference for novel social stimuli, increased repetitive behavior, and increased thigmotaxis in Pten(Y68H/+) six-week-old (P40) mice. In addition, we found significant microglial activation with increased expression of complement and neuroinflammatory proteins in vivo and in vitro accompanied by enhanced phagocytosis. These observations were subsequently validated with RNA-seq and qRT-PCR, which revealed overexpression of many genes involved in neuroinflammation and neuronal function, including oxytocin. Oxytocin transcript was fivefold overexpressed (P?=?0.0018), and oxytocin protein was strongly overexpressed in the Pten(Y68H/+) hypothalamus. CONCLUSIONS: The nuclear-predominant Pten(Y68H/+) model has clarified that Pten dysfunction links to microglial pathology and this associates with increased Akt signaling. We also demonstrate that Pten dysfunction associates with changes in the oxytocin system, an important connection between a prominent ASD risk gene and a potent neuroendocrine regulator of social behavior. These cellular and molecular pathologies may related to the observed changes in social behavior. Ultimately, the findings from this work may reveal important biomarkers and/or novel therapeutic modalities that could be explored in individuals with germline mutations in PTEN with ASD. En ligne : http://dx.doi.org/10.1186/s13229-021-00448-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459
in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA
Titre : Immune Dysfunction in Autism Spectrum Disorder Type de document : Texte imprimé et/ou numérique Auteurs : Natalia V. MALKOVA, Auteur ; Elaine Y. HSIAO, Auteur Année de publication : 2016 Importance : p.65-82 Langues : Anglais (eng) Mots-clés : Autoimmunity Maternal immune activation Microglia Neuroimmunology Neuroinflammation Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Autism spectrum disorder (ASD) is diagnosed based on abnormalities in social, communicative, and stereotyped behaviors, but a preponderance of evidence indicates that immune dysfunction is a key feature of ASD. In this chapter, we review the several cellular and functional immune alterations observed in the brains, periphery, and gastrointestinal tracts of ASD individuals. In addition, we highlight pathways for neuroimmune interactions and novel roles for immune factors in neurodevelopment. We further discuss immune-related environmental and genetic risk factors for ASD, along with findings from animal models that support a role for early life immune dysregulation in the etiopathogenesis of ASD symptoms. Finally, we outline results from clinical trials of immune-based therapies for ASD and consider future directions for investigating potential immune contributions to ASD diagnosis and treatment. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00005-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 Immune Dysfunction in Autism Spectrum Disorder [Texte imprimé et/ou numérique] / Natalia V. MALKOVA, Auteur ; Elaine Y. HSIAO, Auteur . - 2016 . - p.65-82.
in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA
Langues : Anglais (eng)
Mots-clés : Autoimmunity Maternal immune activation Microglia Neuroimmunology Neuroinflammation Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Autism spectrum disorder (ASD) is diagnosed based on abnormalities in social, communicative, and stereotyped behaviors, but a preponderance of evidence indicates that immune dysfunction is a key feature of ASD. In this chapter, we review the several cellular and functional immune alterations observed in the brains, periphery, and gastrointestinal tracts of ASD individuals. In addition, we highlight pathways for neuroimmune interactions and novel roles for immune factors in neurodevelopment. We further discuss immune-related environmental and genetic risk factors for ASD, along with findings from animal models that support a role for early life immune dysregulation in the etiopathogenesis of ASD symptoms. Finally, we outline results from clinical trials of immune-based therapies for ASD and consider future directions for investigating potential immune contributions to ASD diagnosis and treatment. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00005-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 Exemplaires
Code-barres Cote Support Localisation Section Disponibilité aucun exemplaire A pilot open-label trial of minocycline in patients with autism and regressive features / Carlos A. PARDO in Journal of Neurodevelopmental Disorders, 5-1 (December 2013)
[article]
Titre : A pilot open-label trial of minocycline in patients with autism and regressive features Type de document : Texte imprimé et/ou numérique Auteurs : Carlos A. PARDO, Auteur ; A. BUCKLEY, Auteur ; A. THURM, Auteur ; L. C. LEE, Auteur ; A. AZHAGIRI, Auteur ; D. M. NEVILLE, Auteur ; Susan E. SWEDO, Auteur Article en page(s) : p.9 Langues : Anglais (eng) Mots-clés : Autism Bdnf Chemokines Clinical trial Cytokines Metalloproteinases Microglia Minocycline Neuroinflammation Neurotrophins Index. décimale : PER Périodiques Résumé : BACKGROUND: Minocycline is a tetracycline derivative that readily crosses the blood brain barrier and appears to have beneficial effects on neuroinflammation, microglial activation and neuroprotection in a variety of neurological disorders. Both microglial activation and neuroinflammation have been reported to be associated with autism. The study was designed to evaluate the effects of minocycline treatment on markers of neuroinflammation and autism symptomatology in children with autism and a history of developmental regression. METHODS: Eleven children were enrolled in an open-label trial of six months of minocycline (1.4 mg/kg). Ten children completed the trial. Behavioral measures were collected and cerebrospinal fluid (CSF), serum and plasma were obtained before and at the end of minocycline treatment and were analyzed for markers of neuroinflammation. RESULTS: Clinical improvements were negligible. The laboratory assays demonstrated significant changes in the expression profile of the truncated form of brain derived neurotrophic factor (BDNF) (P = 0.042) and hepatic growth factor (HGF) (P = 0.028) in CSF. In serum, the ratio of the truncated BDNF form and alpha-2 macroglobulin (alpha-2 M), was also significantly lower (P = 0.028) while the mature BDNF/alpha-2 M ratio revealed no difference following treatment. Only the chemokine CXCL8 (IL-8) was significantly different (P = 0.047) in serum while no significant changes were observed in CSF or serum in chemokines such as CCL2 (MCP-1) or cytokines such as TNF-alpha, CD40L, IL-6, IFN-gamma and IL-1beta when pre- and post-treatment levels of these proteins were compared. No significant pre- and post-treatment changes were seen in the profiles of plasma metalloproteinases, putative targets of the effects of minocycline. CONCLUSIONS: Changes in the pre- and post-treatment profiles of BDNF in CSF and blood, HGF in CSF and CXCL8 (IL-8) in serum, suggest that minocycline may have effects in the CNS by modulating the production of neurotrophic growth factors. However, in this small group of children, no clinical improvements were observed during or after the six months of minocycline administration. TRIAL REGISTRATION: NCT00409747. En ligne : http://dx.doi.org/10.1186/1866-1955-5-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=345
in Journal of Neurodevelopmental Disorders > 5-1 (December 2013) . - p.9[article] A pilot open-label trial of minocycline in patients with autism and regressive features [Texte imprimé et/ou numérique] / Carlos A. PARDO, Auteur ; A. BUCKLEY, Auteur ; A. THURM, Auteur ; L. C. LEE, Auteur ; A. AZHAGIRI, Auteur ; D. M. NEVILLE, Auteur ; Susan E. SWEDO, Auteur . - p.9.
Langues : Anglais (eng)
in Journal of Neurodevelopmental Disorders > 5-1 (December 2013) . - p.9
Mots-clés : Autism Bdnf Chemokines Clinical trial Cytokines Metalloproteinases Microglia Minocycline Neuroinflammation Neurotrophins Index. décimale : PER Périodiques Résumé : BACKGROUND: Minocycline is a tetracycline derivative that readily crosses the blood brain barrier and appears to have beneficial effects on neuroinflammation, microglial activation and neuroprotection in a variety of neurological disorders. Both microglial activation and neuroinflammation have been reported to be associated with autism. The study was designed to evaluate the effects of minocycline treatment on markers of neuroinflammation and autism symptomatology in children with autism and a history of developmental regression. METHODS: Eleven children were enrolled in an open-label trial of six months of minocycline (1.4 mg/kg). Ten children completed the trial. Behavioral measures were collected and cerebrospinal fluid (CSF), serum and plasma were obtained before and at the end of minocycline treatment and were analyzed for markers of neuroinflammation. RESULTS: Clinical improvements were negligible. The laboratory assays demonstrated significant changes in the expression profile of the truncated form of brain derived neurotrophic factor (BDNF) (P = 0.042) and hepatic growth factor (HGF) (P = 0.028) in CSF. In serum, the ratio of the truncated BDNF form and alpha-2 macroglobulin (alpha-2 M), was also significantly lower (P = 0.028) while the mature BDNF/alpha-2 M ratio revealed no difference following treatment. Only the chemokine CXCL8 (IL-8) was significantly different (P = 0.047) in serum while no significant changes were observed in CSF or serum in chemokines such as CCL2 (MCP-1) or cytokines such as TNF-alpha, CD40L, IL-6, IFN-gamma and IL-1beta when pre- and post-treatment levels of these proteins were compared. No significant pre- and post-treatment changes were seen in the profiles of plasma metalloproteinases, putative targets of the effects of minocycline. CONCLUSIONS: Changes in the pre- and post-treatment profiles of BDNF in CSF and blood, HGF in CSF and CXCL8 (IL-8) in serum, suggest that minocycline may have effects in the CNS by modulating the production of neurotrophic growth factors. However, in this small group of children, no clinical improvements were observed during or after the six months of minocycline administration. TRIAL REGISTRATION: NCT00409747. En ligne : http://dx.doi.org/10.1186/1866-1955-5-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=345