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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)
[article]
Titre : Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism Type de document : Texte imprimé et/ou numérique 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
in Autism Research > 9-3 (March 2016) . - p.350-375[article] Altered Striatal Synaptic Function and Abnormal Behaviour in Shank3 Exon4-9 Deletion Mouse Model of Autism [Texte imprimé et/ou numérique] / 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)
[article]
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 et/ou numérique 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
in Molecular Autism > 11 (2020) . - 70 p.[article] Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome [Texte imprimé et/ou numérique] / 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)
[article]
Titre : Comprehensive Behavioral Phenotyping of a 16p11.2 Del Mouse Model for Neurodevelopmental Disorders Type de document : Texte imprimé et/ou numérique Auteurs : Joseph F. 3rd LYNCH, Auteur ; Sarah L. FERRI, Auteur ; Christopher C. ANGELAKOS, Auteur ; Hannah SCHOCH, Auteur ; Thomas NICKL-JOCKSCHAT, Auteur ; Arnold GONZALEZ, Auteur ; William 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
in Autism Research > 13-10 (October 2020) . - p.1670-1684[article] Comprehensive Behavioral Phenotyping of a 16p11.2 Del Mouse Model for Neurodevelopmental Disorders [Texte imprimé et/ou numérique] / Joseph F. 3rd LYNCH, Auteur ; Sarah L. FERRI, Auteur ; Christopher C. ANGELAKOS, Auteur ; Hannah SCHOCH, Auteur ; Thomas NICKL-JOCKSCHAT, Auteur ; Arnold GONZALEZ, Auteur ; William 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)
[article]
Titre : Effects of Environmental Enrichment on Repetitive Behaviors in the BTBR T+tf/J Mouse Model of Autism Type de document : Texte imprimé et/ou numérique 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
in Autism Research > 6-5 (October 2013) . - p.337-343[article] Effects of Environmental Enrichment on Repetitive Behaviors in the BTBR T+tf/J Mouse Model of Autism [Texte imprimé et/ou numérique] / 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 CIM6P/IGF-2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice / Emmanuel CRUZ in Autism Research, 14-1 (January 2021)
[article]
Titre : CIM6P/IGF-2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice Type de document : Texte imprimé et/ou numérique Auteurs : Emmanuel CRUZ, Auteur ; Giannina DESCALZI, Auteur ; Adam STEINMETZ, Auteur ; Helen E. SCHARFMAN, Auteur ; Aaron KATZMAN, Auteur ; Cristina M. ALBERINI, Auteur Article en page(s) : p.29-45 Langues : Anglais (eng) Mots-clés : Angelman syndrome Ube3a audiogenic seizure cation-independent mannose-6-phosphate receptor insulin-like growth factor 2 insulin-like growth factor 2 receptor mannose-6-phosphate memory motor response mouse model Index. décimale : PER Périodiques Résumé : Angelman syndrome (AS), a genetic disorder that primarily affects the nervous system, is characterized by delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy). No existing therapies are capable of comprehensively treating the deficits in AS; hence, there is an urgent need to identify new treatments. Here we show that insulin-like growth factor 2 (IGF-2) and mannose-6-phosphate (M6P), ligands of two independent binding sites of the cation-independent M6P/IGF-2 receptor (CIM6P/IGF-2R), reverse most major deficits of AS modeled in mice. Subcutaneous injection of IGF-2 or M6P in mice modeling AS restored cognitive impairments as assessed by measurements of contextual and recognition memories, motor deficits assessed by rotarod and hindlimb clasping, and working memory/flexibility measured by Y-maze. IGF-2 also corrected deficits in marble burying and significantly attenuated acoustically induced seizures. An observational battery of tests confirmed that neither ligand changed basic functions including physical characteristics, general behavioral responses, and sensory reflexes, indicating that they are relatively safe. Our data provide strong preclinical evidence that targeting CIM6P/IGF-2R is a promising approach for developing novel therapeutics for AS. LAY SUMMARY: There is no effective treatment for the neurodevelopmental disorder Angelman syndrome (AS). Using a validated AS mouse model, the Ube3a(m-/p+) , in this study we show that systemic administration of ligands of the cation independent mannose-6-phosphate receptor, also known as insulin-like growth factor 2 receptor (CIM6P/IGF-2R) reverses cognitive impairment, motor deficits, as well as seizures associated with AS. Thus, ligands that activate the CIM6P/IGF-2R may represent novel, potential therapeutic targets for AS. En ligne : http://dx.doi.org/10.1002/aur.2418 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=441
in Autism Research > 14-1 (January 2021) . - p.29-45[article] CIM6P/IGF-2 Receptor Ligands Reverse Deficits in Angelman Syndrome Model Mice [Texte imprimé et/ou numérique] / Emmanuel CRUZ, Auteur ; Giannina DESCALZI, Auteur ; Adam STEINMETZ, Auteur ; Helen E. SCHARFMAN, Auteur ; Aaron KATZMAN, Auteur ; Cristina M. ALBERINI, Auteur . - p.29-45.
Langues : Anglais (eng)
in Autism Research > 14-1 (January 2021) . - p.29-45
Mots-clés : Angelman syndrome Ube3a audiogenic seizure cation-independent mannose-6-phosphate receptor insulin-like growth factor 2 insulin-like growth factor 2 receptor mannose-6-phosphate memory motor response mouse model Index. décimale : PER Périodiques Résumé : Angelman syndrome (AS), a genetic disorder that primarily affects the nervous system, is characterized by delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy). No existing therapies are capable of comprehensively treating the deficits in AS; hence, there is an urgent need to identify new treatments. Here we show that insulin-like growth factor 2 (IGF-2) and mannose-6-phosphate (M6P), ligands of two independent binding sites of the cation-independent M6P/IGF-2 receptor (CIM6P/IGF-2R), reverse most major deficits of AS modeled in mice. Subcutaneous injection of IGF-2 or M6P in mice modeling AS restored cognitive impairments as assessed by measurements of contextual and recognition memories, motor deficits assessed by rotarod and hindlimb clasping, and working memory/flexibility measured by Y-maze. IGF-2 also corrected deficits in marble burying and significantly attenuated acoustically induced seizures. An observational battery of tests confirmed that neither ligand changed basic functions including physical characteristics, general behavioral responses, and sensory reflexes, indicating that they are relatively safe. Our data provide strong preclinical evidence that targeting CIM6P/IGF-2R is a promising approach for developing novel therapeutics for AS. LAY SUMMARY: There is no effective treatment for the neurodevelopmental disorder Angelman syndrome (AS). Using a validated AS mouse model, the Ube3a(m-/p+) , in this study we show that systemic administration of ligands of the cation independent mannose-6-phosphate receptor, also known as insulin-like growth factor 2 receptor (CIM6P/IGF-2R) reverses cognitive impairment, motor deficits, as well as seizures associated with AS. Thus, ligands that activate the CIM6P/IGF-2R may represent novel, potential therapeutic targets for AS. En ligne : http://dx.doi.org/10.1002/aur.2418 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=441 Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome: a parallel mouse and human analysis / M. S. SIDOROV in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)
PermalinkGermline nuclear-predominant Pten murine model exhibits impaired social and perseverative behavior, microglial activation, and increased oxytocinergic activity / N. SARN in Molecular Autism, 12 (2021)
PermalinkInsulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome / Elizabeth L. BERG in Molecular Autism, 12 (2021)
PermalinkTargeting the RHOA pathway improves learning and memory in adult Kctd13 and 16p11.2 deletion mouse models / Sandra MARTIN LORENZO in Molecular Autism, 12 (2021)
PermalinkBehavioral profiles of mouse models for autism spectrum disorders / Elodie EY in Autism Research, 4-1 (February 2011)
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