[{"article_number":"110615","file_date_updated":"2022-04-15T09:06:25Z","ec_funded":1,"acknowledgement":"We thank Farnaz Freeman for technical assistance. This research was supported by the Scientific Service Units (SSU) of IST Austria through resources provided by the Bioimaging Facility (BIF) and the Life Science Facility (LSF). This work supported by the European Union’s Horizon 2020 research and innovation program (ERC) grant 715508 to G.N. (REVERSEAUTISM) and grant 825759 to G.T. (ENDpoiNTs); the Fondazione Cariplo 2017-0886 to A.L.T.; E-Rare-3 JTC 2018 IMPACT to M. Gabriele; and the Austrian Science Fund FWF I 4205-B to G.N. Graphical abstract and figures were created using BioRender.com.","year":"2022","pmid":1,"publication_status":"published","publisher":"Elsevier","department":[{"_id":"JoDa"},{"_id":"GaNo"}],"author":[{"full_name":"Villa, Carlo Emanuele","first_name":"Carlo Emanuele","last_name":"Villa"},{"last_name":"Cheroni","first_name":"Cristina","full_name":"Cheroni, Cristina"},{"first_name":"Christoph","last_name":"Dotter","id":"4C66542E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-9033-9096","full_name":"Dotter, Christoph"},{"full_name":"López-Tóbon, Alejandro","last_name":"López-Tóbon","first_name":"Alejandro"},{"last_name":"Oliveira","first_name":"Bárbara","id":"3B03AA1A-F248-11E8-B48F-1D18A9856A87","full_name":"Oliveira, Bárbara"},{"last_name":"Sacco","first_name":"Roberto","id":"42C9F57E-F248-11E8-B48F-1D18A9856A87","full_name":"Sacco, Roberto"},{"id":"365A65F8-F248-11E8-B48F-1D18A9856A87","last_name":"Yahya","first_name":"Aysan Çerağ","full_name":"Yahya, Aysan Çerağ"},{"full_name":"Morandell, Jasmin","id":"4739D480-F248-11E8-B48F-1D18A9856A87","last_name":"Morandell","first_name":"Jasmin"},{"first_name":"Michele","last_name":"Gabriele","full_name":"Gabriele, Michele"},{"full_name":"Tavakoli, Mojtaba","first_name":"Mojtaba","last_name":"Tavakoli","id":"3A0A06F4-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-7667-6854"},{"last_name":"Lyudchik","first_name":"Julia","id":"46E28B80-F248-11E8-B48F-1D18A9856A87","full_name":"Lyudchik, Julia"},{"full_name":"Sommer, Christoph M","last_name":"Sommer","first_name":"Christoph M","orcid":"0000-0003-1216-9105","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Mariano","last_name":"Gabitto","full_name":"Gabitto, Mariano"},{"orcid":"0000-0001-8559-3973","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","last_name":"Danzl","first_name":"Johann G","full_name":"Danzl, Johann G"},{"full_name":"Testa, Giuseppe","last_name":"Testa","first_name":"Giuseppe"},{"full_name":"Novarino, Gaia","first_name":"Gaia","last_name":"Novarino","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-7673-7178"}],"related_material":{"record":[{"id":"12364","relation":"dissertation_contains","status":"public"}]},"date_updated":"2024-03-28T23:30:45Z","date_created":"2022-04-15T09:03:10Z","volume":39,"month":"04","publication_identifier":{"issn":["2211-1247"]},"oa":1,"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"external_id":{"pmid":["35385734"],"isi":["000785983900003"]},"isi":1,"quality_controlled":"1","project":[{"call_identifier":"H2020","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","_id":"25444568-B435-11E9-9278-68D0E5697425","grant_number":"715508"},{"name":"Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy","call_identifier":"FWF","_id":"2690FEAC-B435-11E9-9278-68D0E5697425","grant_number":"I04205"}],"doi":"10.1016/j.celrep.2022.110615","acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"}],"language":[{"iso":"eng"}],"type":"journal_article","abstract":[{"text":"Mutations in the chromodomain helicase DNA-binding 8 (CHD8) gene are a frequent cause of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses macrocephaly, implicating cortical abnormalities, how CHD8 haploinsufficiency affects neurodevelopmental is unclear. Here, employing human cerebral organoids, we find that CHD8 haploinsufficiency disrupted neurodevelopmental trajectories with an accelerated and delayed generation of, respectively, inhibitory and excitatory neurons that yields, at days 60 and 120, symmetrically opposite expansions in their proportions. This imbalance is consistent with an enlargement of cerebral organoids as an in vitro correlate of patients’ macrocephaly. Through an isogenic design of patient-specific mutations and mosaic organoids, we define genotype-phenotype relationships and uncover their cell-autonomous nature. Our results define cell-type-specific CHD8-dependent molecular defects related to an abnormal program of proliferation and alternative splicing. By identifying cell-type-specific effects of CHD8 mutations, our study uncovers reproducible developmental alterations that may be employed for neurodevelopmental disease modeling.","lang":"eng"}],"issue":"1","user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","_id":"11160","title":"CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories","status":"public","ddc":["570"],"intvolume":" 39","file":[{"creator":"dernst","file_size":"7808644","content_type":"application/pdf","file_name":"2022_CellReports_Villa.pdf","access_level":"open_access","date_created":"2022-04-15T09:06:25Z","date_updated":"2022-04-15T09:06:25Z","success":1,"checksum":"b4e8d68f0268dec499af333e6fd5d8e1","file_id":"11164","relation":"main_file"}],"oa_version":"Published Version","keyword":["General Biochemistry","Genetics and Molecular Biology"],"day":"05","article_processing_charge":"Yes","has_accepted_license":"1","publication":"Cell Reports","citation":{"short":"C.E. Villa, C. Cheroni, C. Dotter, A. López-Tóbon, B. Oliveira, R. Sacco, A.Ç. Yahya, J. Morandell, M. Gabriele, M. Tavakoli, J. Lyudchik, C.M. Sommer, M. Gabitto, J.G. Danzl, G. Testa, G. Novarino, Cell Reports 39 (2022).","mla":"Villa, Carlo Emanuele, et al. “CHD8 Haploinsufficiency Links Autism to Transient Alterations in Excitatory and Inhibitory Trajectories.” Cell Reports, vol. 39, no. 1, 110615, Elsevier, 2022, doi:10.1016/j.celrep.2022.110615.","chicago":"Villa, Carlo Emanuele, Cristina Cheroni, Christoph Dotter, Alejandro López-Tóbon, Bárbara Oliveira, Roberto Sacco, Aysan Çerağ Yahya, et al. “CHD8 Haploinsufficiency Links Autism to Transient Alterations in Excitatory and Inhibitory Trajectories.” Cell Reports. Elsevier, 2022. https://doi.org/10.1016/j.celrep.2022.110615.","ama":"Villa CE, Cheroni C, Dotter C, et al. CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Reports. 2022;39(1). doi:10.1016/j.celrep.2022.110615","apa":"Villa, C. E., Cheroni, C., Dotter, C., López-Tóbon, A., Oliveira, B., Sacco, R., … Novarino, G. (2022). CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Reports. Elsevier. https://doi.org/10.1016/j.celrep.2022.110615","ieee":"C. E. Villa et al., “CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories,” Cell Reports, vol. 39, no. 1. Elsevier, 2022.","ista":"Villa CE, Cheroni C, Dotter C, López-Tóbon A, Oliveira B, Sacco R, Yahya AÇ, Morandell J, Gabriele M, Tavakoli M, Lyudchik J, Sommer CM, Gabitto M, Danzl JG, Testa G, Novarino G. 2022. CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Reports. 39(1), 110615."},"article_type":"original","date_published":"2022-04-05T00:00:00Z"},{"oa_version":"Published Version","file":[{"file_name":"220923_Thesis_CDotter_Final.pdf","access_level":"open_access","file_size":20457465,"content_type":"application/pdf","creator":"cchlebak","relation":"main_file","file_id":"12365","embargo":"2023-09-19","date_updated":"2023-09-20T22:30:03Z","date_created":"2023-01-24T13:15:45Z","checksum":"896f4cac9adb6d3f26a6605772f4e1a3"},{"file_id":"12482","relation":"source_file","checksum":"ad01bb20da163be6893b7af832e58419","date_updated":"2023-09-20T22:30:03Z","date_created":"2023-02-02T09:15:35Z","access_level":"closed","file_name":"latex_source_CDotter_Thesis_2022.zip","embargo_to":"open_access","creator":"cchlebak","file_size":22433512,"content_type":"application/x-zip-compressed"}],"title":"Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder","status":"public","ddc":["570"],"user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9","_id":"12364","abstract":[{"text":"Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders character\u0002ized by behavioral symptoms such as problems in social communication and interaction, as\r\nwell as repetitive, restricted behaviors and interests. These disorders show a high degree\r\nof heritability and hundreds of risk genes have been identifed using high throughput\r\nsequencing technologies. This genetic heterogeneity has hampered eforts in understanding\r\nthe pathogenesis of ASD but at the same time given rise to the concept of convergent\r\nmechanisms. Previous studies have identifed that risk genes for ASD broadly converge\r\nonto specifc functional categories with transcriptional regulation being one of the biggest\r\ngroups. In this thesis, I focus on this subgroup of genes and investigate the gene regulatory\r\nconsequences of some of them in the context of neurodevelopment.\r\nFirst, we showed that mutations in the ASD and intellectual disability risk gene Setd5 lead\r\nto perturbations of gene regulatory programs in early cell fate specifcation. In addition,\r\nadult animals display abnormal learning behavior which is mirrored at the transcriptional\r\nlevel by altered activity dependent regulation of postsynaptic gene expression. Lastly,\r\nwe link the regulatory function of Setd5 to its interaction with the Paf1 and the NCoR\r\ncomplex.\r\nSecond, by modeling the heterozygous loss of the top ASD gene CHD8 in human cerebral\r\norganoids we demonstrate profound changes in the developmental trajectories of both\r\ninhibitory and excitatory neurons using single cell RNA-sequencing. While the former\r\nwere generated earlier in CHD8+/- organoids, the generation of the latter was shifted to\r\nlater times in favor of a prolonged progenitor expansion phase and ultimately increased\r\norganoid size.\r\nFinally, by modeling heterozygous mutations for four ASD associated chromatin modifers,\r\nASH1L, KDM6B, KMT5B, and SETD5 in human cortical spheroids we show evidence of\r\nregulatory convergence across three of those genes. We observe a shift from dorsal cortical\r\nexcitatory neuron fates towards partially ventralized cell types resembling cells from the\r\nlateral ganglionic eminence. As this project is still ongoing at the time of writing, future\r\nexperiments will aim at elucidating the regulatory mechanisms underlying this shift with\r\nthe aim of linking these three ASD risk genes through biological convergence.","lang":"eng"}],"alternative_title":["ISTA Thesis"],"type":"dissertation","date_published":"2022-09-19T00:00:00Z","page":"152","citation":{"ieee":"C. Dotter, “Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder,” Institute of Science and Technology Austria, 2022.","apa":"Dotter, C. (2022). Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. Institute of Science and Technology Austria. https://doi.org/10.15479/at:ista:12094","ista":"Dotter C. 2022. Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. Institute of Science and Technology Austria.","ama":"Dotter C. Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. 2022. doi:10.15479/at:ista:12094","chicago":"Dotter, Christoph. “Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder.” Institute of Science and Technology Austria, 2022. https://doi.org/10.15479/at:ista:12094.","short":"C. Dotter, Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder, Institute of Science and Technology Austria, 2022.","mla":"Dotter, Christoph. Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder. Institute of Science and Technology Austria, 2022, doi:10.15479/at:ista:12094."},"has_accepted_license":"1","article_processing_charge":"No","day":"19","date_created":"2023-01-24T13:09:57Z","date_updated":"2023-11-16T13:10:22Z","related_material":{"record":[{"relation":"part_of_dissertation","status":"public","id":"3"},{"status":"public","relation":"part_of_dissertation","id":"11160"}]},"author":[{"id":"4C66542E-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-9033-9096","first_name":"Christoph","last_name":"Dotter","full_name":"Dotter, Christoph"}],"department":[{"_id":"GradSch"},{"_id":"GaNo"}],"publisher":"Institute of Science and Technology Austria","publication_status":"published","year":"2022","ec_funded":1,"file_date_updated":"2023-09-20T22:30:03Z","language":[{"iso":"eng"}],"supervisor":[{"full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","last_name":"Novarino","first_name":"Gaia"}],"degree_awarded":"PhD","doi":"10.15479/at:ista:12094","project":[{"name":"Probing development and reversibility of autism spectrum disorders","grant_number":"401299","_id":"254BA948-B435-11E9-9278-68D0E5697425"},{"name":"Critical windows and reversibility of ASD associated with mutations in chromatin remodelers","grant_number":"707964","_id":"9B91375C-BA93-11EA-9121-9846C619BF3A"},{"grant_number":"715508","_id":"25444568-B435-11E9-9278-68D0E5697425","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","call_identifier":"H2020"},{"grant_number":"I04205","_id":"2690FEAC-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy"}],"oa":1,"publication_identifier":{"issn":["2663-337X"]},"month":"09"},{"scopus_import":"1","has_accepted_license":"1","article_processing_charge":"No","day":"30","citation":{"mla":"Vasic, Verica, et al. “Translating the Role of Mtor-and Ras-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment.” Genes, vol. 12, no. 11, 1746, MDPI, 2021, doi:10.3390/genes12111746.","short":"V. Vasic, M.S.O. Jones, D. Haslinger, L. Knaus, M.J. Schmeisser, G. Novarino, A.G. Chiocchetti, Genes 12 (2021).","chicago":"Vasic, Verica, Mattson S.O. Jones, Denise Haslinger, Lisa Knaus, Michael J. Schmeisser, Gaia Novarino, and Andreas G. Chiocchetti. “Translating the Role of Mtor-and Ras-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment.” Genes. MDPI, 2021. https://doi.org/10.3390/genes12111746.","ama":"Vasic V, Jones MSO, Haslinger D, et al. Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment. Genes. 2021;12(11). doi:10.3390/genes12111746","ista":"Vasic V, Jones MSO, Haslinger D, Knaus L, Schmeisser MJ, Novarino G, Chiocchetti AG. 2021. Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment. Genes. 12(11), 1746.","ieee":"V. Vasic et al., “Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment,” Genes, vol. 12, no. 11. MDPI, 2021.","apa":"Vasic, V., Jones, M. S. O., Haslinger, D., Knaus, L., Schmeisser, M. J., Novarino, G., & Chiocchetti, A. G. (2021). Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment. Genes. MDPI. https://doi.org/10.3390/genes12111746"},"publication":"Genes","article_type":"original","date_published":"2021-10-30T00:00:00Z","type":"journal_article","alternative_title":["Special Issue \"From Genes to Therapy in Autism Spectrum Disorder\""],"issue":"11","abstract":[{"lang":"eng","text":"Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems"}],"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","_id":"10281","intvolume":" 12","ddc":["570"],"status":"public","title":"Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment","file":[{"file_id":"11380","relation":"main_file","success":1,"checksum":"256cb832a9c3051c7dc741f6423b8cbd","date_created":"2022-05-16T07:02:27Z","date_updated":"2022-05-16T07:02:27Z","access_level":"open_access","file_name":"2021_Genes_Vasic.pdf","creator":"dernst","file_size":1335308,"content_type":"application/pdf"}],"oa_version":"Published Version","publication_identifier":{"eissn":["2073-4425"]},"month":"10","oa":1,"tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"external_id":{"isi":["000834044200002"]},"project":[{"grant_number":"715508","_id":"25444568-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models"},{"name":"Molecular Drug Targets","call_identifier":"FWF","grant_number":"W1232-B24","_id":"2548AE96-B435-11E9-9278-68D0E5697425"}],"quality_controlled":"1","isi":1,"doi":"10.3390/genes12111746","language":[{"iso":"eng"}],"article_number":"1746","ec_funded":1,"file_date_updated":"2022-05-16T07:02:27Z","acknowledgement":"This review was funded by the IMI2 Initiative under the grant AIMS-2-TRIALS No 777394, by the Hessian Ministry for Science and Arts; State of Hesse Ministry for Science and Arts: LOEWE-Grant to the CePTER-Consortium (www.uni-frankfurt.de/67689811); Research (BMBF) under the grant RAISE-genic No 779282 all to AGC. This work was also supported by the European Union’s Horizon 2020 research and innovation program (ERC) grant 715508 (REVERSEAUTISM) and by the Austrian Science Fund (FWF) (DK W1232-B24) both to G.N. and both BMBF GeNeRARe 01GM1519A and CRC 1080, project B10, of the German Research Foundation (DFG) to M.J.S, respectively. We want to thank R. Waltes for her support in preparing this manuscript.","year":"2021","publisher":"MDPI","department":[{"_id":"GaNo"}],"publication_status":"published","author":[{"full_name":"Vasic, Verica","last_name":"Vasic","first_name":"Verica"},{"full_name":"Jones, Mattson S.O.","first_name":"Mattson S.O.","last_name":"Jones"},{"full_name":"Haslinger, Denise","first_name":"Denise","last_name":"Haslinger","id":"76922BDA-3D3B-11EA-90BD-A44F3DDC885E"},{"full_name":"Knaus, Lisa","last_name":"Knaus","first_name":"Lisa","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Schmeisser, Michael J.","first_name":"Michael J.","last_name":"Schmeisser"},{"full_name":"Novarino, Gaia","first_name":"Gaia","last_name":"Novarino","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-7673-7178"},{"full_name":"Chiocchetti, Andreas G.","first_name":"Andreas G.","last_name":"Chiocchetti"}],"volume":12,"date_created":"2021-11-14T23:01:24Z","date_updated":"2023-08-14T11:46:12Z"},{"keyword":["general immunology and microbiology","general biochemistry","genetics and molecular biology","general medicine","general neuroscience"],"has_accepted_license":"1","article_processing_charge":"No","day":"17","citation":{"short":"M.J. Conde-Dusman, P.N. Dey, Ó. Elía-Zudaire, L.E. Garcia Rabaneda, C. García-Lira, T. Grand, V. Briz, E.R. Velasco, R. Andero Galí, S. Niñerola, A. Barco, P. Paoletti, J.F. Wesseling, F. Gardoni, S.J. Tavalin, I. Perez-Otaño, ELife 10 (2021).","mla":"Conde-Dusman, María J., et al. “Control of Protein Synthesis and Memory by GluN3A-NMDA Receptors through Inhibition of GIT1/MTORC1 Assembly.” ELife, vol. 10, e71575, eLife Sciences Publications, 2021, doi:10.7554/elife.71575.","chicago":"Conde-Dusman, María J, Partha N Dey, Óscar Elía-Zudaire, Luis E Garcia Rabaneda, Carmen García-Lira, Teddy Grand, Victor Briz, et al. “Control of Protein Synthesis and Memory by GluN3A-NMDA Receptors through Inhibition of GIT1/MTORC1 Assembly.” ELife. eLife Sciences Publications, 2021. https://doi.org/10.7554/elife.71575.","ama":"Conde-Dusman MJ, Dey PN, Elía-Zudaire Ó, et al. Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly. eLife. 2021;10. doi:10.7554/elife.71575","apa":"Conde-Dusman, M. J., Dey, P. N., Elía-Zudaire, Ó., Garcia Rabaneda, L. E., García-Lira, C., Grand, T., … Perez-Otaño, I. (2021). Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly. ELife. eLife Sciences Publications. https://doi.org/10.7554/elife.71575","ieee":"M. J. Conde-Dusman et al., “Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly,” eLife, vol. 10. eLife Sciences Publications, 2021.","ista":"Conde-Dusman MJ, Dey PN, Elía-Zudaire Ó, Garcia Rabaneda LE, García-Lira C, Grand T, Briz V, Velasco ER, Andero Galí R, Niñerola S, Barco A, Paoletti P, Wesseling JF, Gardoni F, Tavalin SJ, Perez-Otaño I. 2021. Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly. eLife. 10, e71575."},"publication":"eLife","article_type":"original","date_published":"2021-11-17T00:00:00Z","type":"journal_article","abstract":[{"lang":"eng","text":"De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement."}],"_id":"10301","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","intvolume":" 10","status":"public","title":"Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly","ddc":["570"],"file":[{"date_created":"2021-11-18T07:02:02Z","date_updated":"2021-11-18T07:02:02Z","success":1,"checksum":"59318e9e41507cec83c2f4070e6ad540","file_id":"10302","relation":"main_file","creator":"lgarciar","content_type":"application/pdf","file_size":2477302,"file_name":"elife-71575-v1.pdf","access_level":"open_access"}],"oa_version":"Published Version","publication_identifier":{"issn":["2050-084X"]},"month":"11","tmp":{"name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png"},"oa":1,"external_id":{"isi":["000720945900001"]},"isi":1,"quality_controlled":"1","doi":"10.7554/elife.71575","language":[{"iso":"eng"}],"article_number":"e71575","file_date_updated":"2021-11-18T07:02:02Z","acknowledgement":"We thank Stuart Lipton and Nobuki Nakanishi for providing the Grin3a knockout mice, Beverly Davidson for the AAV-caRheb, Jose Esteban for help with behavioral and biochemical experiments, and Noelia Campillo, Rebeca Martínez-Turrillas, and Ana Navarro for expert technical help. Work was funded by the UTE project CIMA; fellowships from the Fundación Tatiana Pérez de Guzmán el Bueno, FEBS, and IBRO (to M.J.C.D.), Generalitat Valenciana (to O.E.-Z.), Juan de la Cierva (to L.G.R.), FPI-MINECO (to E.R.V., to S.N.) and Intertalentum postdoctoral program (to V.B.); ANR (GluBrain3A) and ERC Advanced Grants (#693021) (to P.P.); Ramón y Cajal program RYC2014-15784, RETOS-MINECO SAF2016-76565-R, ERANET-Neuron JTC 2019 ISCIII AC19/00077 FEDER funds (to R.A.); RETOS-MINECO SAF2017-87928-R (to A.B.); an NIH grant (NS76637) and UTHSC College of Medicine funds (to S.J.T.); and NARSAD Independent Investigator Award and grants from the MINECO (CSD2008-00005, SAF2013-48983R, SAF2016-80895-R), Generalitat Valenciana (PROMETEO 2019/020)(to I.P.O.) and Severo-Ochoa Excellence Awards (SEV-2013-0317, SEV-2017-0723).","year":"2021","department":[{"_id":"GaNo"}],"publisher":"eLife Sciences Publications","publication_status":"published","author":[{"full_name":"Conde-Dusman, María J","first_name":"María J","last_name":"Conde-Dusman"},{"last_name":"Dey","first_name":"Partha N","full_name":"Dey, Partha N"},{"first_name":"Óscar","last_name":"Elía-Zudaire","full_name":"Elía-Zudaire, Óscar"},{"first_name":"Luis E","last_name":"Garcia Rabaneda","id":"33D1B084-F248-11E8-B48F-1D18A9856A87","full_name":"Garcia Rabaneda, Luis E"},{"full_name":"García-Lira, Carmen","first_name":"Carmen","last_name":"García-Lira"},{"full_name":"Grand, Teddy","first_name":"Teddy","last_name":"Grand"},{"full_name":"Briz, Victor","first_name":"Victor","last_name":"Briz"},{"full_name":"Velasco, Eric R","last_name":"Velasco","first_name":"Eric R"},{"first_name":"Raül","last_name":"Andero Galí","full_name":"Andero Galí, Raül"},{"full_name":"Niñerola, Sergio","first_name":"Sergio","last_name":"Niñerola"},{"last_name":"Barco","first_name":"Angel","full_name":"Barco, Angel"},{"full_name":"Paoletti, Pierre","last_name":"Paoletti","first_name":"Pierre"},{"first_name":"John F","last_name":"Wesseling","full_name":"Wesseling, John F"},{"last_name":"Gardoni","first_name":"Fabrizio","full_name":"Gardoni, Fabrizio"},{"full_name":"Tavalin, Steven J","first_name":"Steven J","last_name":"Tavalin"},{"first_name":"Isabel","last_name":"Perez-Otaño","full_name":"Perez-Otaño, Isabel"}],"volume":10,"date_created":"2021-11-18T06:59:45Z","date_updated":"2023-08-14T11:50:50Z"},{"doi":"10.1016/j.bbi.2021.07.022","language":[{"iso":"eng"}],"oa":1,"main_file_link":[{"open_access":"1","url":"https://www.zora.uzh.ch/id/eprint/208855/1/ZORA208855.pdf"}],"external_id":{"isi":["000702878400007"],"pmid":["34343616"]},"quality_controlled":"1","isi":1,"publication_identifier":{"issn":["0889-1591"]},"month":"10","author":[{"full_name":"Picard, Katherine","first_name":"Katherine","last_name":"Picard"},{"full_name":"Bisht, Kanchan","first_name":"Kanchan","last_name":"Bisht"},{"full_name":"Poggini, Silvia","first_name":"Silvia","last_name":"Poggini"},{"full_name":"Garofalo, Stefano","first_name":"Stefano","last_name":"Garofalo"},{"full_name":"Golia, Maria Teresa","last_name":"Golia","first_name":"Maria Teresa"},{"full_name":"Basilico, Bernadette","first_name":"Bernadette","last_name":"Basilico","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","orcid":"0000-0003-1843-3173"},{"last_name":"Abdallah","first_name":"Fatima","full_name":"Abdallah, Fatima"},{"last_name":"Ciano Albanese","first_name":"Naomi","full_name":"Ciano Albanese, Naomi"},{"last_name":"Amrein","first_name":"Irmgard","full_name":"Amrein, Irmgard"},{"last_name":"Vernoux","first_name":"Nathalie","full_name":"Vernoux, Nathalie"},{"last_name":"Sharma","first_name":"Kaushik","full_name":"Sharma, Kaushik"},{"first_name":"Chin Wai","last_name":"Hui","full_name":"Hui, Chin Wai"},{"full_name":"C. Savage, Julie","last_name":"C. Savage","first_name":"Julie"},{"full_name":"Limatola, Cristina","last_name":"Limatola","first_name":"Cristina"},{"full_name":"Ragozzino, Davide","first_name":"Davide","last_name":"Ragozzino"},{"full_name":"Maggi, Laura","first_name":"Laura","last_name":"Maggi"},{"last_name":"Branchi","first_name":"Igor","full_name":"Branchi, Igor"},{"full_name":"Tremblay, Marie Ève","last_name":"Tremblay","first_name":"Marie Ève"}],"volume":97,"date_created":"2021-08-22T22:01:21Z","date_updated":"2023-10-03T09:49:18Z","pmid":1,"acknowledgement":"We acknowledge that Université Laval stands on the traditional and unceded land of the Huron-Wendat peoples; and that the University of Victoria exists on the territory of the Lekwungen peoples and that the Songhees, Esquimalt and WSÁNEÆ peoples have relationships to this land. We thank Emmanuel Planel for the access to the epifluorescence microscope and Julie-Christine Lévesque at the Bioimaging Platform of CRCHU de Québec-Université Laval for technical assistance. We also thank the Centre for Advanced Materials and Related Technology for the access to the confocal microscope with Airyscan. K.P. was supported by a doctoral scholarship from Fonds de Recherche du Québec – Santé (FRQS), an excellence award from Fondation du CHU de Québec, as well as from Centre Thématique de Recherche en Neurosciences and from Fondation Famille-Choquette. K.B. was supported by excellence scholarships from Université Laval and Fondation du CHU de Québec. S.G. is supported by FIRC-AIRC fellowship for Italy 22329/2018 and by Pilot ARISLA NKINALS 2019. C.W.H. and J.C.S. were supported by postdoctoral fellowships from FRQS. This study was funded by a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grant (RGPIN-2014-05308) awarded to M.E.T., by ERANET neuron 2017 MicroSynDep to M.E.T. and I.B., and by the Italian Ministry of Health, grant RF-2018-12367249 to I.B, by PRIN 2017, AIRC 2019 and Ministero della Salute RF2018 to C.L. M.E.T. is a Tier II Canada Research Chair in Neurobiology of Aging and Cognition.","year":"2021","department":[{"_id":"GaNo"}],"publisher":"Elsevier","publication_status":"published","date_published":"2021-10-01T00:00:00Z","citation":{"ama":"Picard K, Bisht K, Poggini S, et al. Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice. Brain, Behavior, and Immunity. 2021;97:423-439. doi:10.1016/j.bbi.2021.07.022","ista":"Picard K, Bisht K, Poggini S, Garofalo S, Golia MT, Basilico B, Abdallah F, Ciano Albanese N, Amrein I, Vernoux N, Sharma K, Hui CW, C. Savage J, Limatola C, Ragozzino D, Maggi L, Branchi I, Tremblay MÈ. 2021. Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice. Brain, Behavior, and Immunity. 97, 423–439.","ieee":"K. Picard et al., “Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice,” Brain, Behavior, and Immunity, vol. 97. Elsevier, pp. 423–439, 2021.","apa":"Picard, K., Bisht, K., Poggini, S., Garofalo, S., Golia, M. T., Basilico, B., … Tremblay, M. È. (2021). Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice. Brain, Behavior, and Immunity. Elsevier. https://doi.org/10.1016/j.bbi.2021.07.022","mla":"Picard, Katherine, et al. “Microglial-Glucocorticoid Receptor Depletion Alters the Response of Hippocampal Microglia and Neurons in a Chronic Unpredictable Mild Stress Paradigm in Female Mice.” Brain, Behavior, and Immunity, vol. 97, Elsevier, 2021, pp. 423–39, doi:10.1016/j.bbi.2021.07.022.","short":"K. Picard, K. Bisht, S. Poggini, S. Garofalo, M.T. Golia, B. Basilico, F. Abdallah, N. Ciano Albanese, I. Amrein, N. Vernoux, K. Sharma, C.W. Hui, J. C. Savage, C. Limatola, D. Ragozzino, L. Maggi, I. Branchi, M.È. Tremblay, Brain, Behavior, and Immunity 97 (2021) 423–439.","chicago":"Picard, Katherine, Kanchan Bisht, Silvia Poggini, Stefano Garofalo, Maria Teresa Golia, Bernadette Basilico, Fatima Abdallah, et al. “Microglial-Glucocorticoid Receptor Depletion Alters the Response of Hippocampal Microglia and Neurons in a Chronic Unpredictable Mild Stress Paradigm in Female Mice.” Brain, Behavior, and Immunity. Elsevier, 2021. https://doi.org/10.1016/j.bbi.2021.07.022."},"publication":"Brain, Behavior, and Immunity","page":"423-439","article_type":"original","article_processing_charge":"No","day":"01","scopus_import":"1","oa_version":"Submitted Version","_id":"9953","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","intvolume":" 97","title":"Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice","status":"public","abstract":[{"lang":"eng","text":"Chronic psychological stress is one of the most important triggers and environmental risk factors for neuropsychiatric disorders. Chronic stress can influence all organs via the secretion of stress hormones, including glucocorticoids by the adrenal glands, which coordinate the stress response across the body. In the brain, glucocorticoid receptors (GR) are expressed by various cell types including microglia, which are its resident immune cells regulating stress-induced inflammatory processes. To study the roles of microglial GR under normal homeostatic conditions and following chronic stress, we generated a mouse model in which the GR gene is depleted in microglia specifically at adulthood to prevent developmental confounds. We first confirmed that microglia were depleted in GR in our model in males and females among the cingulate cortex and the hippocampus, both stress-sensitive brain regions. Then, cohorts of microglial-GR depleted and wild-type (WT) adult female mice were housed for 3 weeks in a standard or stressful condition, using a chronic unpredictable mild stress (CUMS) paradigm. CUMS induced stress-related behavior in both microglial-GR depleted and WT animals as demonstrated by a decrease of both saccharine preference and progressive ratio breakpoint. Nevertheless, the hippocampal microglial and neural mechanisms underlying the adaptation to stress occurred differently between the two genotypes. Upon CUMS exposure, microglial morphology was altered in the WT controls, without any apparent effect in microglial-GR depleted mice. Furthermore, in the standard environment condition, GR depleted-microglia showed increased expression of pro-inflammatory genes, and genes involved in microglial homeostatic functions (such as Trem2, Cx3cr1 and Mertk). On the contrary, in CUMS condition, GR depleted-microglia showed reduced expression levels of pro-inflammatory genes and increased neuroprotective as well as anti-inflammatory genes compared to WT-microglia. Moreover, in microglial-GR depleted mice, but not in WT mice, CUMS led to a significant reduction of CA1 long-term potentiation and paired-pulse ratio. Lastly, differences in adult hippocampal neurogenesis were observed between the genotypes during normal homeostatic conditions, with microglial-GR deficiency increasing the formation of newborn neurons in the dentate gyrus subgranular zone independently from stress exposure. Together, these findings indicate that, although the deletion of microglial GR did not prevent the animal’s ability to respond to stress, it contributed to modulating hippocampal functions in both standard and stressful conditions, notably by shaping the microglial response to chronic stress."}],"type":"journal_article"}]