20 recherche sur le mot-clé 'Mouse model'

Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism / Thomas C. JARAMILLO in Autism Research, 9-3 (March 2016)  

Public ISBD [article]  inAutism Research > 9-3 (March 2016) . - p.350-375 Titre : Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism Type de document : texte imprimé Auteurs : Thomas C. JARAMILLO, Auteur ; Haley E. SPEED, Auteur ; Zhong XUAN, Auteur ; Jeremy M. REIMERS, Auteur ; Shunan LIU, Auteur ; Craig M. POWELL, Auteur Article en page(s) : p.350-375 Langues : Anglais (eng) Mots-clés : autism spectrum disorder  Shank3  Phelan-McDermid syndrome  mouse model  grooming Index. décimale : PER Périodiques Résumé : Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3e4-9 KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3e4-9 heterozygous (HET) and Shank3e4-9 KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3e4-9 KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3e4-9 KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3e4-9 HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3e4-9 KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3e4-9 mutant mouse model of autism. Autism Res 2016, 9: 350–375. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1529 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=285 [article] Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism [texte imprimé] / Thomas C. JARAMILLO, Auteur ; Haley E. SPEED, Auteur ; Zhong XUAN, Auteur ; Jeremy M. REIMERS, Auteur ; Shunan LIU, Auteur ; Craig M. POWELL, Auteur . - p.350-375. Langues : Anglais (eng) in Autism Research > 9-3 (March 2016) . - p.350-375 Mots-clés : autism spectrum disorder  Shank3  Phelan-McDermid syndrome  mouse model  grooming Index. décimale : PER Périodiques Résumé : Shank3 is a multi-domain, synaptic scaffolding protein that organizes proteins in the postsynaptic density of excitatory synapses. Clinical studies suggest that ∼0.5% of autism spectrum disorder (ASD) cases may involve SHANK3 mutation/deletion. Patients with SHANK3 mutations exhibit deficits in cognition along with delayed/impaired speech/language and repetitive and obsessive/compulsive-like (OCD-like) behaviors. To examine how mutation/deletion of SHANK3 might alter brain function leading to ASD, we have independently created mice with deletion of Shank3 exons 4-9, a region implicated in ASD patients. We find that homozygous deletion of exons 4-9 (Shank3e4-9 KO) results in loss of the two highest molecular weight isoforms of Shank3 and a significant reduction in other isoforms. Behaviorally, both Shank3e4-9 heterozygous (HET) and Shank3e4-9 KO mice display increased repetitive grooming, deficits in novel and spatial object recognition learning and memory, and abnormal ultrasonic vocalizations. Shank3e4-9 KO mice also display abnormal social interaction when paired with one another. Analysis of synaptosome fractions from striata of Shank3e4-9 KO mice reveals decreased Homer1b/c, GluA2, and GluA3 expression. Both Shank3e4-9 HET and KO demonstrated a significant reduction in NMDA/AMPA ratio at excitatory synapses onto striatal medium spiny neurons. Furthermore, Shank3e4-9 KO mice displayed reduced hippocampal LTP despite normal baseline synaptic transmission. Collectively these behavioral, biochemical and physiological changes suggest Shank3 isoforms have region-specific roles in regulation of AMPAR subunit localization and NMDAR function in the Shank3e4-9 mutant mouse model of autism. Autism Res 2016, 9: 350–375. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1529 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=285

Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome / Monica SONZOGNI in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 70 p. Titre : Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome Type de document : texte imprimé Auteurs : Monica SONZOGNI, Auteur ; Peipei ZHAI, Auteur ; Edwin J. MIENTJES, Auteur ; Geeske M. VAN WOERDEN, Auteur ; Ype ELGERSMA, Auteur Article en page(s) : 70 p. Langues : Anglais (eng) Mots-clés : ASO therapy  Angelman syndrome  Behavior  Critical period  Mouse model  Ube3a Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of functional ubiquitin protein ligase E3A (UBE3A). In neurons, UBE3A expression is tightly regulated by a mechanism of imprinting which suppresses the expression of the paternal UBE3A allele. Promising treatment strategies for AS are directed at activating paternal UBE3A gene expression. However, for such strategies to be successful, it is important to know when such a treatment should start, and how much UBE3A expression is needed for normal embryonic brain development. METHODS: Using a conditional mouse model of AS, we further delineated the critical period for UBE3A expression during early brain development. Ube3a gene expression was induced around the second week of gestation and mouse phenotypes were assessed using a behavioral test battery. To investigate the requirements of embryonic UBE3A expression, we made use of mice in which the paternal Ube3a allele was deleted. RESULTS: We observed a full behavioral rescue of the AS mouse model phenotypes when Ube3a gene reactivation was induced around the start of the last week of mouse embryonic development. We found that full silencing of the paternal Ube3a allele was not completed till the first week after birth but that deletion of the paternal Ube3a allele had no significant effect on the assessed phenotypes. LIMITATIONS: Direct translation to human is limited, as we do not precisely know how human and mouse brain development aligns over gestational time. Moreover, many of the assessed phenotypes have limited translational value, as the underlying brain regions involved in these tasks are largely unknown. CONCLUSIONS: Our findings provide further important insights in the requirement of UBE3A expression during brain development. We found that loss of up to 50% of UBE3A protein during prenatal mouse brain development does not significantly impact the assessed mouse behavioral phenotypes. Together with previous findings, our results indicate that the most critical function for mouse UBE3A lies in the early postnatal period between birth and P21. En ligne : http://dx.doi.org/10.1186/s13229-020-00376-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433 [article] Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome [texte imprimé] / Monica SONZOGNI, Auteur ; Peipei ZHAI, Auteur ; Edwin J. MIENTJES, Auteur ; Geeske M. VAN WOERDEN, Auteur ; Ype ELGERSMA, Auteur . - 70 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 70 p. Mots-clés : ASO therapy  Angelman syndrome  Behavior  Critical period  Mouse model  Ube3a Index. décimale : PER Périodiques Résumé : BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of functional ubiquitin protein ligase E3A (UBE3A). In neurons, UBE3A expression is tightly regulated by a mechanism of imprinting which suppresses the expression of the paternal UBE3A allele. Promising treatment strategies for AS are directed at activating paternal UBE3A gene expression. However, for such strategies to be successful, it is important to know when such a treatment should start, and how much UBE3A expression is needed for normal embryonic brain development. METHODS: Using a conditional mouse model of AS, we further delineated the critical period for UBE3A expression during early brain development. Ube3a gene expression was induced around the second week of gestation and mouse phenotypes were assessed using a behavioral test battery. To investigate the requirements of embryonic UBE3A expression, we made use of mice in which the paternal Ube3a allele was deleted. RESULTS: We observed a full behavioral rescue of the AS mouse model phenotypes when Ube3a gene reactivation was induced around the start of the last week of mouse embryonic development. We found that full silencing of the paternal Ube3a allele was not completed till the first week after birth but that deletion of the paternal Ube3a allele had no significant effect on the assessed phenotypes. LIMITATIONS: Direct translation to human is limited, as we do not precisely know how human and mouse brain development aligns over gestational time. Moreover, many of the assessed phenotypes have limited translational value, as the underlying brain regions involved in these tasks are largely unknown. CONCLUSIONS: Our findings provide further important insights in the requirement of UBE3A expression during brain development. We found that loss of up to 50% of UBE3A protein during prenatal mouse brain development does not significantly impact the assessed mouse behavioral phenotypes. Together with previous findings, our results indicate that the most critical function for mouse UBE3A lies in the early postnatal period between birth and P21. En ligne : http://dx.doi.org/10.1186/s13229-020-00376-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=433

Comprehensive Behavioral Phenotyping of a 16p11.2 Del Mouse Model for Neurodevelopmental Disorders / Joseph F. 3rd LYNCH in Autism Research, 13-10 (October 2020)  

Public ISBD [article]  inAutism Research > 13-10 (October 2020) . - p.1670-1684 Titre : Comprehensive Behavioral Phenotyping of a 16p11.2 Del Mouse Model for Neurodevelopmental Disorders Type de document : texte imprimé Auteurs : Joseph F. 3rd LYNCH, Auteur ; Sarah L. FERRI, Auteur ; Christopher C. ANGELAKOS, Auteur ; Hannah SCHOCH, Auteur ; Thomas NICKL-JOCKSCHAT, Auteur ; Arnold GONZALEZ, Auteur ; W. Timothy O'BRIEN, Auteur ; Ted ABEL, Auteur Article en page(s) : p.1670-1684 Langues : Anglais (eng) Mots-clés : 16p11.2  autism spectrum disorders  behavior  copy number variant  mouse model  neurodevelopmental disorders  phenotype Index. décimale : PER Périodiques Résumé : The microdeletion of copy number variant 16p11.2 is one of the most common genetic mutations associated with neurodevelopmental disorders, such as Autism Spectrum Disorders (ASDs). Here, we describe our comprehensive behavioral phenotyping of the 16p11.2 deletion line developed by Alea Mills on a C57BL/6J and 129S1/SvImJ F1 background (Del(m) ). Male and female Del(m) mice were tested in developmental milestones as preweanlings (PND2-PND12), and were tested in open field activity, elevated zero maze, rotarod, novel object recognition, fear conditioning, social approach, and other measures during post-weaning (PND21), adolescence (PND42), and adulthood (>PND70). Developmentally, Del(m) mice show distinct weight reduction that persists into adulthood. Del(m) males also have reduced grasp reflexes and limb strength during development, but no other reflexive deficits whereas Del(m) females show limb strength deficits and decreased sensitivity to heat. In a modified version of a rotarod task that measures balance and coordinated motor activity, Del(m) males, but not females, show improved performance at high speeds. Del(m) males and females also show age-specific reductions in anxiety-like behavior compared with WTs, but neither sex show deficits in a social preference task. When assessing learning and memory, Del(m) males and females show age-specific impairments in a novel object or spatial object recognition, but no deficits in contextual fear memory. This work extends the understanding of the behavioral phenotypes seen with 16p11.2 deletion by emphasizing age and sex-specific deficits; important variables to consider when studying mouse models for neurodevelopmental disorders. LAY SUMMARY: Autism spectrum disorder is a common neurodevelopmental disorder that causes repetitive behavior and impairments in social interaction and communication. Here, we assess the effects of one of the most common genetic alterations in ASDs, a deletion of one copy of 29 genes, using a mouse model. These animals show differences in behavior between males and females and across ages compared with control animals, including changes in development, cognition, and motor coordination. Autism Res 2020, 13: 1670-1684. © 2020 International Society for Autism Research and Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2357 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=431 [article] Comprehensive Behavioral Phenotyping of a 16p11.2 Del Mouse Model for Neurodevelopmental Disorders [texte imprimé] / Joseph F. 3rd LYNCH, Auteur ; Sarah L. FERRI, Auteur ; Christopher C. ANGELAKOS, Auteur ; Hannah SCHOCH, Auteur ; Thomas NICKL-JOCKSCHAT, Auteur ; Arnold GONZALEZ, Auteur ; W. Timothy O'BRIEN, Auteur ; Ted ABEL, Auteur . - p.1670-1684. Langues : Anglais (eng) in Autism Research > 13-10 (October 2020) . - p.1670-1684 Mots-clés : 16p11.2  autism spectrum disorders  behavior  copy number variant  mouse model  neurodevelopmental disorders  phenotype Index. décimale : PER Périodiques Résumé : The microdeletion of copy number variant 16p11.2 is one of the most common genetic mutations associated with neurodevelopmental disorders, such as Autism Spectrum Disorders (ASDs). Here, we describe our comprehensive behavioral phenotyping of the 16p11.2 deletion line developed by Alea Mills on a C57BL/6J and 129S1/SvImJ F1 background (Del(m) ). Male and female Del(m) mice were tested in developmental milestones as preweanlings (PND2-PND12), and were tested in open field activity, elevated zero maze, rotarod, novel object recognition, fear conditioning, social approach, and other measures during post-weaning (PND21), adolescence (PND42), and adulthood (>PND70). Developmentally, Del(m) mice show distinct weight reduction that persists into adulthood. Del(m) males also have reduced grasp reflexes and limb strength during development, but no other reflexive deficits whereas Del(m) females show limb strength deficits and decreased sensitivity to heat. In a modified version of a rotarod task that measures balance and coordinated motor activity, Del(m) males, but not females, show improved performance at high speeds. Del(m) males and females also show age-specific reductions in anxiety-like behavior compared with WTs, but neither sex show deficits in a social preference task. When assessing learning and memory, Del(m) males and females show age-specific impairments in a novel object or spatial object recognition, but no deficits in contextual fear memory. This work extends the understanding of the behavioral phenotypes seen with 16p11.2 deletion by emphasizing age and sex-specific deficits; important variables to consider when studying mouse models for neurodevelopmental disorders. LAY SUMMARY: Autism spectrum disorder is a common neurodevelopmental disorder that causes repetitive behavior and impairments in social interaction and communication. Here, we assess the effects of one of the most common genetic alterations in ASDs, a deletion of one copy of 29 genes, using a mouse model. These animals show differences in behavior between males and females and across ages compared with control animals, including changes in development, cognition, and motor coordination. Autism Res 2020, 13: 1670-1684. © 2020 International Society for Autism Research and Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2357 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=431

Effects of Environmental Enrichment on Repetitive Behaviors in the BTBR T+tf/J Mouse Model of Autism / Stacey REYNOLDS in Autism Research, 6-5 (October 2013)  

Public ISBD [article]  inAutism Research > 6-5 (October 2013) . - p.337-343 Titre : Effects of Environmental Enrichment on Repetitive Behaviors in the BTBR T+tf/J Mouse Model of Autism Type de document : texte imprimé Auteurs : Stacey REYNOLDS, Auteur ; Meagan URRUELA, Auteur ; Darragh P. DEVINE, Auteur Article en page(s) : p.337-343 Langues : Anglais (eng) Mots-clés : autism  BTBR inbred strain  environmental enrichment  mouse model  repetitive behavior  stereotypy Index. décimale : PER Périodiques Résumé : Lower order and higher order repetitive behaviors have been documented in the BTBR T+tf/J (BTBR) mouse strain, a mouse model that exhibits all three core behavioral domains that define autism. The purpose of this study was to evaluate the effectiveness of environmental enrichment for reducing repetitive behaviors in BTBR mice. Lower order behaviors were captured by assaying the time and sequence of grooming, while higher order behaviors were measured using pattern analysis of an object exploration task from digital recordings. Baseline scores were established at 7 weeks of age, followed by 30 days of housing in either a standard or enriched cage. As expected, BTBR mice spent significantly more time grooming and had a more rigid grooming sequence than control C57BL/6J mice did at baseline. After 30 days of enrichment housing, BTBR mice demonstrated a significant reduction in time spent grooming, resulting in levels that were lower than those exhibited by BTBR mice in standard housing. However, no changes were noted in the rigidity of their grooming sequence. In contrast to previous findings, there was no difference in repetitive patterns of exploration at baseline between BTBR and C57BL/6J mice in the object exploration test. Subsequently, enrichment did not significantly alter the number of repetitive patterns at posttest. Overall, the results suggest that environmental enrichment may be beneficial for reducing the time spent engaging in lower order repetitive behaviors, but may not change the overall quality of the behaviors when they do manifest. En ligne : http://dx.doi.org/10.1002/aur.1298 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=218 [article] Effects of Environmental Enrichment on Repetitive Behaviors in the BTBR T+tf/J Mouse Model of Autism [texte imprimé] / Stacey REYNOLDS, Auteur ; Meagan URRUELA, Auteur ; Darragh P. DEVINE, Auteur . - p.337-343. Langues : Anglais (eng) in Autism Research > 6-5 (October 2013) . - p.337-343 Mots-clés : autism  BTBR inbred strain  environmental enrichment  mouse model  repetitive behavior  stereotypy Index. décimale : PER Périodiques Résumé : Lower order and higher order repetitive behaviors have been documented in the BTBR T+tf/J (BTBR) mouse strain, a mouse model that exhibits all three core behavioral domains that define autism. The purpose of this study was to evaluate the effectiveness of environmental enrichment for reducing repetitive behaviors in BTBR mice. Lower order behaviors were captured by assaying the time and sequence of grooming, while higher order behaviors were measured using pattern analysis of an object exploration task from digital recordings. Baseline scores were established at 7 weeks of age, followed by 30 days of housing in either a standard or enriched cage. As expected, BTBR mice spent significantly more time grooming and had a more rigid grooming sequence than control C57BL/6J mice did at baseline. After 30 days of enrichment housing, BTBR mice demonstrated a significant reduction in time spent grooming, resulting in levels that were lower than those exhibited by BTBR mice in standard housing. However, no changes were noted in the rigidity of their grooming sequence. In contrast to previous findings, there was no difference in repetitive patterns of exploration at baseline between BTBR and C57BL/6J mice in the object exploration test. Subsequently, enrichment did not significantly alter the number of repetitive patterns at posttest. Overall, the results suggest that environmental enrichment may be beneficial for reducing the time spent engaging in lower order repetitive behaviors, but may not change the overall quality of the behaviors when they do manifest. En ligne : http://dx.doi.org/10.1002/aur.1298 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=218

Pharmacological inhibition of the CB1 cannabinoid receptor restores abnormal brain mitochondrial CB1 receptor expression and rescues bioenergetic and cognitive defects in a female mouse model of Rett syndrome / Livia COSENTINO in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 39p. Titre : Pharmacological inhibition of the CB1 cannabinoid receptor restores abnormal brain mitochondrial CB1 receptor expression and rescues bioenergetic and cognitive defects in a female mouse model of Rett syndrome Type de document : texte imprimé Auteurs : Livia COSENTINO, Auteur ; Chiara URBINATI, Auteur ; Chiara LANZILLOTTA, Auteur ; Domenico DE RASMO, Auteur ; Daniela VALENTI, Auteur ; Mattia PELLAS, Auteur ; Maria Cristina QUATTRINI, Auteur ; Fabiana PISCITELLI, Auteur ; Magdalena KOSTRZEWA, Auteur ; Fabio DI DOMENICO, Auteur ; Donatella PIETRAFORTE, Auteur ; Tiziana BISOGNO, Auteur ; Anna SIGNORILE, Auteur ; Rosa Anna VACCA, Auteur ; Bianca DE FILIPPIS, Auteur Article en page(s) : 39p. Langues : Anglais (eng) Mots-clés : Animals  Female  Mice  Brain/metabolism/drug effects  Disease Models, Animal  Energy Metabolism/drug effects  Methyl-CpG-Binding Protein 2/metabolism/genetics  Mitochondria/metabolism/drug effects  Receptor, Cannabinoid, CB1/metabolism/genetics/antagonists & inhibitors  Rett Syndrome/metabolism/drug therapy/genetics  Rimonabant/pharmacology  Brain mitochondria  CB1 cannabinoid receptor  Energy metabolism  Intellectual disability  Mouse model  Pka  Rett syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Defective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary receptor subtype of the endocannabinoid system in the brain, is located on brain mitochondrial membranes (mtCB1R), where it can locally regulate energy production, synaptic transmission and memory abilities through the inhibition of the intra-mitochondrial protein kinase A (mtPKA). In the present study, we asked whether an overactive mtCB1R-mtPKA signaling might underlie the brain mitochondrial alterations in RTT and whether its modulation by systemic administration of the CB1R inverse agonist rimonabant might improve bioenergetics and cognitive defects in mice modeling RTT. METHODS: Rimonabant (0.3 mg/kg/day, intraperitoneal injections) was administered daily to symptomatic female mice carrying a truncating mutation of the Mecp2 gene and its effects on brain mitochondria functionality, systemic oxidative status, and memory function were assessed. RESULTS: mtCB1R is overexpressed in the RTT mouse brain. Subchronic treatment with rimonabant normalizes mtCB1R expression in RTT mouse brains, boosts mtPKA signaling, and restores the defective brain mitochondrial bioenergetics, abnormal peripheral redox homeostasis, and impaired cognitive abilities in RTT mice. LIMITATIONS: The lack of selectivity of the rimonabant treatment towards mtCB1R does not allow us to exclude that the beneficial effects exerted by the treatment in the RTT mouse model may be ascribed more broadly to the modulation of CB1R activity and distribution among intracellular compartments, rather than to a selective effect on mtCB1R-mediated signaling. The low sample size of few experiments is a further limitation that has been addressed replicating the main findings under different experimental conditions. CONCLUSIONS: The present data identify mtCB1R overexpression as a novel molecular alteration in the RTT mouse brain that may underlie defective brain mitochondrial bioenergetics and cognitive dysfunction. En ligne : https://dx.doi.org/10.1186/s13229-024-00617-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Pharmacological inhibition of the CB1 cannabinoid receptor restores abnormal brain mitochondrial CB1 receptor expression and rescues bioenergetic and cognitive defects in a female mouse model of Rett syndrome [texte imprimé] / Livia COSENTINO, Auteur ; Chiara URBINATI, Auteur ; Chiara LANZILLOTTA, Auteur ; Domenico DE RASMO, Auteur ; Daniela VALENTI, Auteur ; Mattia PELLAS, Auteur ; Maria Cristina QUATTRINI, Auteur ; Fabiana PISCITELLI, Auteur ; Magdalena KOSTRZEWA, Auteur ; Fabio DI DOMENICO, Auteur ; Donatella PIETRAFORTE, Auteur ; Tiziana BISOGNO, Auteur ; Anna SIGNORILE, Auteur ; Rosa Anna VACCA, Auteur ; Bianca DE FILIPPIS, Auteur . - 39p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 39p. Mots-clés : Animals  Female  Mice  Brain/metabolism/drug effects  Disease Models, Animal  Energy Metabolism/drug effects  Methyl-CpG-Binding Protein 2/metabolism/genetics  Mitochondria/metabolism/drug effects  Receptor, Cannabinoid, CB1/metabolism/genetics/antagonists & inhibitors  Rett Syndrome/metabolism/drug therapy/genetics  Rimonabant/pharmacology  Brain mitochondria  CB1 cannabinoid receptor  Energy metabolism  Intellectual disability  Mouse model  Pka  Rett syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Defective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary receptor subtype of the endocannabinoid system in the brain, is located on brain mitochondrial membranes (mtCB1R), where it can locally regulate energy production, synaptic transmission and memory abilities through the inhibition of the intra-mitochondrial protein kinase A (mtPKA). In the present study, we asked whether an overactive mtCB1R-mtPKA signaling might underlie the brain mitochondrial alterations in RTT and whether its modulation by systemic administration of the CB1R inverse agonist rimonabant might improve bioenergetics and cognitive defects in mice modeling RTT. METHODS: Rimonabant (0.3 mg/kg/day, intraperitoneal injections) was administered daily to symptomatic female mice carrying a truncating mutation of the Mecp2 gene and its effects on brain mitochondria functionality, systemic oxidative status, and memory function were assessed. RESULTS: mtCB1R is overexpressed in the RTT mouse brain. Subchronic treatment with rimonabant normalizes mtCB1R expression in RTT mouse brains, boosts mtPKA signaling, and restores the defective brain mitochondrial bioenergetics, abnormal peripheral redox homeostasis, and impaired cognitive abilities in RTT mice. LIMITATIONS: The lack of selectivity of the rimonabant treatment towards mtCB1R does not allow us to exclude that the beneficial effects exerted by the treatment in the RTT mouse model may be ascribed more broadly to the modulation of CB1R activity and distribution among intracellular compartments, rather than to a selective effect on mtCB1R-mediated signaling. The low sample size of few experiments is a further limitation that has been addressed replicating the main findings under different experimental conditions. CONCLUSIONS: The present data identify mtCB1R overexpression as a novel molecular alteration in the RTT mouse brain that may underlie defective brain mitochondrial bioenergetics and cognitive dysfunction. En ligne : https://dx.doi.org/10.1186/s13229-024-00617-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

The BTBR T+ Itpr3tf/J mouse strain as a model to study the genetic, immune, and metabolic origins of neurodevelopmental disorders / M.P. VISCOMI in Research in Autism Spectrum Disorders, 119 (January 2025)  

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UBE3A reinstatement restores behaviorand proteome in an Angelman syndrome mouse model of imprinting defects / Claudia MILAZZO in Molecular Autism, 16 (2025)  

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CIM6P/IGF-2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice / Emmanuel CRUZ in Autism Research, 14-1 (January 2021)  

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Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome: a parallel mouse and human analysis / Michael S. SIDOROV in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)  

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Germline nuclear-predominant Pten murine model exhibits impaired social and perseverative behavior, microglial activation, and increased oxytocinergic activity / Nick SARN in Molecular Autism, 12 (2021)  

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