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Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain / Y. HARA in Molecular Autism, 8 (2017)
[article]
Titre : Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain Type de document : Texte imprimé et/ou numérique Auteurs : Y. HARA, Auteur ; Yukio AGO, Auteur ; E. TAKANO, Auteur ; S. HASEBE, Auteur ; T. NAKAZAWA, Auteur ; H. HASHIMOTO, Auteur ; T. MATSUDA, Auteur ; K. TAKUMA, Auteur Article en page(s) : 33p. Langues : Anglais (eng) Mots-clés : Autism mouse model Embryonic brain MicroRNA Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: MicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain. RESULTS: Prenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain. CONCLUSIONS: These findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure. En ligne : http://dx.doi.org/10.1186/s13229-017-0149-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330
in Molecular Autism > 8 (2017) . - 33p.[article] Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain [Texte imprimé et/ou numérique] / Y. HARA, Auteur ; Yukio AGO, Auteur ; E. TAKANO, Auteur ; S. HASEBE, Auteur ; T. NAKAZAWA, Auteur ; H. HASHIMOTO, Auteur ; T. MATSUDA, Auteur ; K. TAKUMA, Auteur . - 33p.
Langues : Anglais (eng)
in Molecular Autism > 8 (2017) . - 33p.
Mots-clés : Autism mouse model Embryonic brain MicroRNA Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: MicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain. RESULTS: Prenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain. CONCLUSIONS: These findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure. En ligne : http://dx.doi.org/10.1186/s13229-017-0149-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 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