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Mouse Models of Tuberous Sclerosis / Dan EHNINGER
Titre : Mouse Models of Tuberous Sclerosis Type de document : Texte imprimé et/ou numérique Auteurs : Dan EHNINGER, Auteur Année de publication : 2015 Importance : p.431-450 Langues : Anglais (eng) Mots-clés : Tuberous sclerosis Gene targeting NMDA mTOR Rapamycin Glutamate Index. décimale : AUT-B AUT-B - L'Autisme - Ouvrages généraux et scientifiques Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=265 Mouse Models of Tuberous Sclerosis [Texte imprimé et/ou numérique] / Dan EHNINGER, Auteur . - 2015 . - p.431-450.
Langues : Anglais (eng)
Mots-clés : Tuberous sclerosis Gene targeting NMDA mTOR Rapamycin Glutamate Index. décimale : AUT-B AUT-B - L'Autisme - Ouvrages généraux et scientifiques Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=265 Exemplaires
Code-barres Cote Support Localisation Section Disponibilité aucun exemplaire A brain proteomic investigation of rapamycin effects in the Tsc1(+/-) mouse model / H. WESSELING in Molecular Autism, 8 (2017)
[article]
Titre : A brain proteomic investigation of rapamycin effects in the Tsc1(+/-) mouse model Type de document : Texte imprimé et/ou numérique Auteurs : H. WESSELING, Auteur ; Y. ELGERSMA, Auteur ; S. BAHN, Auteur Article en page(s) : 41p. Langues : Anglais (eng) Mots-clés : Animal model Proteomics Rapamycin Srm Tuberous sclerosis Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a rare monogenic disorder characterized by benign tumors in multiple organs as well as a high prevalence of epilepsy, intellectual disability and autism. TSC is caused by inactivating mutations in the TSC1 or TSC2 genes. Heterozygocity induces hyperactivation of mTOR which can be inhibited by mTOR inhibitors, such as rapamycin, which have proven efficacy in the treatment of TSC-associated symptoms. The aim of the present study was (1) to identify molecular changes associated with social and cognitive deficits in the brain tissue of Tsc1(+/-) mice and (2) to investigate the molecular effects of rapamycin treatment, which has been shown to ameliorate genotype-related behavioural deficits. METHODS: Molecular alterations in the frontal cortex and hippocampus of Tsc1(+/-) and control mice, with or without rapamycin treatment, were investigated. A quantitative mass spectrometry-based shotgun proteomic approach (LC-MS(E)) was employed as an unbiased method to detect changes in protein levels. Changes identified in the initial profiling stage were validated using selected reaction monitoring (SRM). Protein Set Enrichment Analysis was employed to identify dysregulated pathways. RESULTS: LC-MS(E) analysis of Tsc1(+/-) mice and controls (n = 30) identified 51 proteins changed in frontal cortex and 108 in the hippocampus. Bioinformatic analysis combined with targeted proteomic validation revealed several dysregulated molecular pathways. Using targeted assays, proteomic alterations in the hippocampus validated the pathways "myelination", "dendrite," and "oxidative stress", an upregulation of ribosomal proteins and the mTOR kinase. LC-MS(E) analysis was also employed on Tsc1(+/-) and wildtype mice (n = 34) treated with rapamycin or vehicle. Rapamycin treatment exerted a stronger proteomic effect in Tsc1(+/-) mice with significant changes (mainly decreased expression) in 231 and 106 proteins, respectively. The cellular pathways "oxidative stress" and "apoptosis" were found to be affected in Tsc1(+/-) mice and the cellular compartments "myelin sheet" and "neurofilaments" were affected by rapamycin treatment. Thirty-three proteins which were altered in Tsc1(+/-) mice were normalized following rapamycin treatment, amongst them oxidative stress related proteins, myelin-specific and ribosomal proteins. CONCLUSIONS: Molecular changes in the Tsc1(+/-) mouse brain were more prominent in the hippocampus compared to the frontal cortex. Pathways linked to myelination and oxidative stress response were prominently affected and, at least in part, normalized following rapamycin treatment. The results could aid in the identification of novel drug targets for the treatment of cognitive, social and psychiatric symptoms in autism spectrum disorders. Similar pathways have also been implicated in other psychiatric and neurodegenerative disorders and could imply similar disease processes. Thus, the potential efficacy of mTOR inhibitors warrants further investigation not only for autism spectrum disorders but also for other neuropsychiatric and neurodegenerative diseases. En ligne : http://dx.doi.org/10.1186/s13229-017-0151-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331
in Molecular Autism > 8 (2017) . - 41p.[article] A brain proteomic investigation of rapamycin effects in the Tsc1(+/-) mouse model [Texte imprimé et/ou numérique] / H. WESSELING, Auteur ; Y. ELGERSMA, Auteur ; S. BAHN, Auteur . - 41p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 41p.
Mots-clés : Animal model Proteomics Rapamycin Srm Tuberous sclerosis Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a rare monogenic disorder characterized by benign tumors in multiple organs as well as a high prevalence of epilepsy, intellectual disability and autism. TSC is caused by inactivating mutations in the TSC1 or TSC2 genes. Heterozygocity induces hyperactivation of mTOR which can be inhibited by mTOR inhibitors, such as rapamycin, which have proven efficacy in the treatment of TSC-associated symptoms. The aim of the present study was (1) to identify molecular changes associated with social and cognitive deficits in the brain tissue of Tsc1(+/-) mice and (2) to investigate the molecular effects of rapamycin treatment, which has been shown to ameliorate genotype-related behavioural deficits. METHODS: Molecular alterations in the frontal cortex and hippocampus of Tsc1(+/-) and control mice, with or without rapamycin treatment, were investigated. A quantitative mass spectrometry-based shotgun proteomic approach (LC-MS(E)) was employed as an unbiased method to detect changes in protein levels. Changes identified in the initial profiling stage were validated using selected reaction monitoring (SRM). Protein Set Enrichment Analysis was employed to identify dysregulated pathways. RESULTS: LC-MS(E) analysis of Tsc1(+/-) mice and controls (n = 30) identified 51 proteins changed in frontal cortex and 108 in the hippocampus. Bioinformatic analysis combined with targeted proteomic validation revealed several dysregulated molecular pathways. Using targeted assays, proteomic alterations in the hippocampus validated the pathways "myelination", "dendrite," and "oxidative stress", an upregulation of ribosomal proteins and the mTOR kinase. LC-MS(E) analysis was also employed on Tsc1(+/-) and wildtype mice (n = 34) treated with rapamycin or vehicle. Rapamycin treatment exerted a stronger proteomic effect in Tsc1(+/-) mice with significant changes (mainly decreased expression) in 231 and 106 proteins, respectively. The cellular pathways "oxidative stress" and "apoptosis" were found to be affected in Tsc1(+/-) mice and the cellular compartments "myelin sheet" and "neurofilaments" were affected by rapamycin treatment. Thirty-three proteins which were altered in Tsc1(+/-) mice were normalized following rapamycin treatment, amongst them oxidative stress related proteins, myelin-specific and ribosomal proteins. CONCLUSIONS: Molecular changes in the Tsc1(+/-) mouse brain were more prominent in the hippocampus compared to the frontal cortex. Pathways linked to myelination and oxidative stress response were prominently affected and, at least in part, normalized following rapamycin treatment. The results could aid in the identification of novel drug targets for the treatment of cognitive, social and psychiatric symptoms in autism spectrum disorders. Similar pathways have also been implicated in other psychiatric and neurodegenerative disorders and could imply similar disease processes. Thus, the potential efficacy of mTOR inhibitors warrants further investigation not only for autism spectrum disorders but also for other neuropsychiatric and neurodegenerative diseases. En ligne : http://dx.doi.org/10.1186/s13229-017-0151-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism-like neurobehavioral phenotype in a rat model / Viera KUTNA in Autism Research, 15-5 (May 2022)
[article]
Titre : Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism-like neurobehavioral phenotype in a rat model Type de document : Texte imprimé et/ou numérique Auteurs : Viera KUTNA, Auteur ; Valerie BRID O'LEARY, Auteur ; Cyril HOSCHL, Auteur ; Saak V. OVSEPIAN, Auteur Article en page(s) : p.791-805 Langues : Anglais (eng) Mots-clés : Animals Autism Spectrum Disorder Autistic Disorder Cerebellum/metabolism Demyelinating Diseases/complications/metabolism Epilepsy/complications Humans Mechanistic Target of Rapamycin Complex 1/genetics/metabolism Phenotype Rats Tuberous Sclerosis Purkinje neurons cerebellum demyelination mTORC1 signaling microglia activation synaptophysin Index. décimale : PER Périodiques Résumé : The cerebellum hosts more than half of all neurons of the human brain, with their organized activity playing a key role in coordinating motor functions. Cerebellar activity has also been implicated in the control of speech, communication, and social behavior, which are compromised in autism spectrum disorders (ASD). Despite major research advances, there is a shortage of mechanistic data relating cellular and molecular changes in the cerebellum to autistic behavior. We studied the impact of tuberous sclerosis complex 2 haploinsufficiency (Tsc2+/-) with downstream mTORC1 hyperactivity on cerebellar morphology and cellular organization in 1, 9, and 18?m.o. Eker rats, to determine possible structural correlates of an autism-like behavioural phenotype in this model. We report a greater developmental expansion of the cerebellar vermis, owing to enlarged white matter and thickened molecular layer. Histochemical and immunofluorescence data suggest age-related demyelination of central tract of the vermis, as evident from reduced level of myelin-basic protein in the arbora vitae. We also observed a higher number of astrocytes in Tsc2+/- rats of older age while the number of Purkinje cells (PCs) in these animals was lower than in wild-type controls. Unlike astrocytes and PCs, Bergmann glia remained unaltered at all ages in both genotypes, while the number of microglia was higher in Tsc2+/- rats of older age. The convergent evidence for a variety of age-dependent cellular changes in the cerebellum of rats associated with mTORC1 hyperactivity, thus, predicts an array of functional impairments, which may contribute to the developmental onset of an autism-like behavioral phenotype in this model. LAY SUMMARY: This study elucidates the impact of constitutive mTORC1 hyperactivity on cerebellar morphology and cellular organization in a rat model of autism and epilepsy. It describes age-dependent degeneration of Purkinje neurons, with demyelination of central tract as well as activation of microglia, and discusses the implications of these changes for neuro-behavioral phenotypes. The described changes provide new indications for the putative mechanisms underlying cerebellar impairments with their age-related onset, which may contribute to the pathobiology of autism, epilepsy, and related disorders. En ligne : http://dx.doi.org/10.1002/aur.2688 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473
in Autism Research > 15-5 (May 2022) . - p.791-805[article] Cerebellar demyelination and neurodegeneration associated with mTORC1 hyperactivity may contribute to the developmental onset of autism-like neurobehavioral phenotype in a rat model [Texte imprimé et/ou numérique] / Viera KUTNA, Auteur ; Valerie BRID O'LEARY, Auteur ; Cyril HOSCHL, Auteur ; Saak V. OVSEPIAN, Auteur . - p.791-805.
Langues : Anglais (eng)
in Autism Research > 15-5 (May 2022) . - p.791-805
Mots-clés : Animals Autism Spectrum Disorder Autistic Disorder Cerebellum/metabolism Demyelinating Diseases/complications/metabolism Epilepsy/complications Humans Mechanistic Target of Rapamycin Complex 1/genetics/metabolism Phenotype Rats Tuberous Sclerosis Purkinje neurons cerebellum demyelination mTORC1 signaling microglia activation synaptophysin Index. décimale : PER Périodiques Résumé : The cerebellum hosts more than half of all neurons of the human brain, with their organized activity playing a key role in coordinating motor functions. Cerebellar activity has also been implicated in the control of speech, communication, and social behavior, which are compromised in autism spectrum disorders (ASD). Despite major research advances, there is a shortage of mechanistic data relating cellular and molecular changes in the cerebellum to autistic behavior. We studied the impact of tuberous sclerosis complex 2 haploinsufficiency (Tsc2+/-) with downstream mTORC1 hyperactivity on cerebellar morphology and cellular organization in 1, 9, and 18?m.o. Eker rats, to determine possible structural correlates of an autism-like behavioural phenotype in this model. We report a greater developmental expansion of the cerebellar vermis, owing to enlarged white matter and thickened molecular layer. Histochemical and immunofluorescence data suggest age-related demyelination of central tract of the vermis, as evident from reduced level of myelin-basic protein in the arbora vitae. We also observed a higher number of astrocytes in Tsc2+/- rats of older age while the number of Purkinje cells (PCs) in these animals was lower than in wild-type controls. Unlike astrocytes and PCs, Bergmann glia remained unaltered at all ages in both genotypes, while the number of microglia was higher in Tsc2+/- rats of older age. The convergent evidence for a variety of age-dependent cellular changes in the cerebellum of rats associated with mTORC1 hyperactivity, thus, predicts an array of functional impairments, which may contribute to the developmental onset of an autism-like behavioral phenotype in this model. LAY SUMMARY: This study elucidates the impact of constitutive mTORC1 hyperactivity on cerebellar morphology and cellular organization in a rat model of autism and epilepsy. It describes age-dependent degeneration of Purkinje neurons, with demyelination of central tract as well as activation of microglia, and discusses the implications of these changes for neuro-behavioral phenotypes. The described changes provide new indications for the putative mechanisms underlying cerebellar impairments with their age-related onset, which may contribute to the pathobiology of autism, epilepsy, and related disorders. En ligne : http://dx.doi.org/10.1002/aur.2688 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=473 Tsc1 haploinsufficiency in Nkx2.1 cells upregulates hippocampal interneuron mTORC1 activity, impairs pyramidal cell synaptic inhibition, and alters contextual fear discrimination and spatial working memory in mice / Nabila HAJI in Molecular Autism, 11 (2020)
[article]
Titre : Tsc1 haploinsufficiency in Nkx2.1 cells upregulates hippocampal interneuron mTORC1 activity, impairs pyramidal cell synaptic inhibition, and alters contextual fear discrimination and spatial working memory in mice Type de document : Texte imprimé et/ou numérique Auteurs : Nabila HAJI, Auteur ; Ilse RIEBE, Auteur ; Argel AGUILAR-VALLES, Auteur ; Julien ARTINIAN, Auteur ; Isabel LAPLANTE, Auteur ; Jean-Claude LACAILLE, Auteur Article en page(s) : 29 p. Langues : Anglais (eng) Mots-clés : Autism mouse model Contextual fear conditioning Inhibitory interneurons Spatial learning Tuberous sclerosis Whole-cell recordings mTORC1 Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in TSC1 or TSC2 genes cause tuberous sclerosis complex (TSC), a disorder associated with epilepsy, autism, and intellectual disability. TSC1 and TSC2 are repressors of the mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of protein synthesis. Dysregulation of mTORC1 in TSC mouse models leads to impairments in excitation-inhibition balance, synaptic plasticity, and hippocampus-dependent learning and memory deficits. However, synaptic inhibition arises from multiple types of inhibitory interneurons and how changes in specific interneurons contribute to TSC remains largely unknown. In the present work, we determined the effect of conditional Tsc1 haploinsufficiency in a specific subgroup of inhibitory cells on hippocampal function in mice. METHODS: We investigated the consequences of conditional heterozygous knockout of Tsc1 in MGE-derived inhibitory cells by crossing Nkx2.1(Cre/wt);Tsc1(f/f) mice. We examined the changes in mTORC1 activity and synaptic transmission in hippocampal cells, as well as hippocampus-related cognitive tasks. RESULTS: We detected selective increases in phosphorylation of ribosomal protein S6 in interneurons, indicating cell-specific-upregulated mTORC1 signaling. At the behavioral level, Nkx2.1(Cre/wt);Tsc1(f/wt) mice exhibited intact contextual fear memory, but impaired contextual fear discrimination. They displayed intact spatial learning and reference memory but impairment in spatial working memory. Whole-cell recordings in hippocampal slices of Nkx2.1(Cre/wt);Tsc1(f/wt) mice showed intact basic membrane properties, as well as miniature excitatory and inhibitory synaptic transmission, in pyramidal and Nkx2.1-expressing inhibitory cells. Using optogenetic activation of Nkx2.1 interneurons in slices of Nkx2.1(Cre/wt);Tsc1(f/wt) mice, we found a decrease in synaptic inhibition of pyramidal cells. Chronic, but not acute treatment, with the mTORC1 inhibitor rapamycin reversed the impairment in synaptic inhibition. CONCLUSIONS: Our results indicate that Tsc1 haploinsufficiency in MGE-derived inhibitory cells upregulates mTORC1 activity in these interneurons, reduces their synaptic inhibition of pyramidal cells, and alters contextual fear discrimination and spatial working memory. Thus, selective dysregulation of mTORC1 function in Nkx2.1-expressing inhibitory cells appears sufficient to impair synaptic inhibition and contributes to cognitive deficits in the Tsc1 mouse model of TSC. En ligne : http://dx.doi.org/10.1186/s13229-020-00340-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427
in Molecular Autism > 11 (2020) . - 29 p.[article] Tsc1 haploinsufficiency in Nkx2.1 cells upregulates hippocampal interneuron mTORC1 activity, impairs pyramidal cell synaptic inhibition, and alters contextual fear discrimination and spatial working memory in mice [Texte imprimé et/ou numérique] / Nabila HAJI, Auteur ; Ilse RIEBE, Auteur ; Argel AGUILAR-VALLES, Auteur ; Julien ARTINIAN, Auteur ; Isabel LAPLANTE, Auteur ; Jean-Claude LACAILLE, Auteur . - 29 p.
Langues : Anglais (eng)
in Molecular Autism > 11 (2020) . - 29 p.
Mots-clés : Autism mouse model Contextual fear conditioning Inhibitory interneurons Spatial learning Tuberous sclerosis Whole-cell recordings mTORC1 Index. décimale : PER Périodiques Résumé : BACKGROUND: Mutations in TSC1 or TSC2 genes cause tuberous sclerosis complex (TSC), a disorder associated with epilepsy, autism, and intellectual disability. TSC1 and TSC2 are repressors of the mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of protein synthesis. Dysregulation of mTORC1 in TSC mouse models leads to impairments in excitation-inhibition balance, synaptic plasticity, and hippocampus-dependent learning and memory deficits. However, synaptic inhibition arises from multiple types of inhibitory interneurons and how changes in specific interneurons contribute to TSC remains largely unknown. In the present work, we determined the effect of conditional Tsc1 haploinsufficiency in a specific subgroup of inhibitory cells on hippocampal function in mice. METHODS: We investigated the consequences of conditional heterozygous knockout of Tsc1 in MGE-derived inhibitory cells by crossing Nkx2.1(Cre/wt);Tsc1(f/f) mice. We examined the changes in mTORC1 activity and synaptic transmission in hippocampal cells, as well as hippocampus-related cognitive tasks. RESULTS: We detected selective increases in phosphorylation of ribosomal protein S6 in interneurons, indicating cell-specific-upregulated mTORC1 signaling. At the behavioral level, Nkx2.1(Cre/wt);Tsc1(f/wt) mice exhibited intact contextual fear memory, but impaired contextual fear discrimination. They displayed intact spatial learning and reference memory but impairment in spatial working memory. Whole-cell recordings in hippocampal slices of Nkx2.1(Cre/wt);Tsc1(f/wt) mice showed intact basic membrane properties, as well as miniature excitatory and inhibitory synaptic transmission, in pyramidal and Nkx2.1-expressing inhibitory cells. Using optogenetic activation of Nkx2.1 interneurons in slices of Nkx2.1(Cre/wt);Tsc1(f/wt) mice, we found a decrease in synaptic inhibition of pyramidal cells. Chronic, but not acute treatment, with the mTORC1 inhibitor rapamycin reversed the impairment in synaptic inhibition. CONCLUSIONS: Our results indicate that Tsc1 haploinsufficiency in MGE-derived inhibitory cells upregulates mTORC1 activity in these interneurons, reduces their synaptic inhibition of pyramidal cells, and alters contextual fear discrimination and spatial working memory. Thus, selective dysregulation of mTORC1 function in Nkx2.1-expressing inhibitory cells appears sufficient to impair synaptic inhibition and contributes to cognitive deficits in the Tsc1 mouse model of TSC. En ligne : http://dx.doi.org/10.1186/s13229-020-00340-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427