[{"abstract":[{"text":"Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction.","lang":"eng"}],"acknowledged_ssus":[{"_id":"PreCl"},{"_id":"EM-Fac"},{"_id":"Bio"},{"_id":"LifeSc"}],"oa_version":"Published Version","scopus_import":"1","intvolume":" 186","month":"04","publication_status":"published","publication_identifier":{"issn":["0092-8674"]},"language":[{"iso":"eng"}],"file":[{"file_name":"2023_Cell_Knaus.pdf","date_created":"2023-05-02T09:26:21Z","file_size":15712841,"date_updated":"2023-05-02T09:26:21Z","creator":"dernst","success":1,"checksum":"47e94fbe19e86505b429cb7a5b503ce6","file_id":"12889","content_type":"application/pdf","relation":"main_file","access_level":"open_access"}],"ec_funded":1,"related_material":{"link":[{"url":"https://ista.ac.at/en/news/feed-them-or-lose-them/","relation":"press_release","description":"News on ISTA Website"}],"record":[{"id":"13107","status":"public","relation":"dissertation_contains"}]},"issue":"9","volume":186,"_id":"12802","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","article_type":"original","keyword":["General Biochemistry","Genetics and Molecular Biology"],"status":"public","date_updated":"2024-02-07T08:03:32Z","ddc":["570"],"file_date_updated":"2023-05-02T09:26:21Z","department":[{"_id":"SiHi"},{"_id":"GaNo"}],"acknowledgement":"We thank A. Freeman and V. Voronin for technical assistance, S. Deixler, A. Stichelberger, M. Schunn, and the Preclinical Facility for managing our animal colony. We thank L. Andersen and J. Sonntag, who were involved in generating the MADM lines. We thank the ISTA LSF Mass Spectrometry Core Facility for assistance with the proteomic analysis, as well as the ISTA electron microscopy and Imaging and Optics facility for technical support. Metabolomics LC-MS/MS analysis was performed by the Metabolomics Facility at Vienna BioCenter Core Facilities (VBCF). We acknowledge the support of the EMBL Metabolomics Core Facility (MCF) for lipidomics and intracellular metabolomics mass spectrometry data acquisition and analysis. RNA sequencing was performed by the Next Generation Sequencing Facility at VBCF. Schematics were generated using Biorender.com. This work was supported by the Austrian Science Fund (FWF, DK W1232-B24) and by the European Union’s Horizon 2020 research and innovation program (ERC) grant 725780 (LinPro) to S.H. and 715508 (REVERSEAUTISM) to G.N.","oa":1,"quality_controlled":"1","publisher":"Elsevier","year":"2023","isi":1,"has_accepted_license":"1","publication":"Cell","day":"27","page":"1950-1967.e25","date_created":"2023-04-05T08:15:40Z","doi":"10.1016/j.cell.2023.02.037","date_published":"2023-04-27T00:00:00Z","project":[{"_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Molecular Drug Targets","grant_number":"W1232-B24"},{"name":"Principles of Neural Stem Cell Lineage Progression in Cerebral Cortex Development","grant_number":"725780","_id":"260018B0-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"},{"_id":"25444568-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","grant_number":"715508","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models"}],"citation":{"mla":"Knaus, Lisa, et al. “Large Neutral Amino Acid Levels Tune Perinatal Neuronal Excitability and Survival.” Cell, vol. 186, no. 9, Elsevier, 2023, p. 1950–1967.e25, doi:10.1016/j.cell.2023.02.037.","ama":"Knaus L, Basilico B, Malzl D, et al. Large neutral amino acid levels tune perinatal neuronal excitability and survival. Cell. 2023;186(9):1950-1967.e25. doi:10.1016/j.cell.2023.02.037","apa":"Knaus, L., Basilico, B., Malzl, D., Gerykova Bujalkova, M., Smogavec, M., Schwarz, L. A., … Novarino, G. (2023). Large neutral amino acid levels tune perinatal neuronal excitability and survival. Cell. Elsevier. https://doi.org/10.1016/j.cell.2023.02.037","short":"L. Knaus, B. Basilico, D. Malzl, M. Gerykova Bujalkova, M. Smogavec, L.A. Schwarz, S. Gorkiewicz, N. Amberg, F. Pauler, C. Knittl-Frank, M. Tassinari, N. Maulide, T. Rülicke, J. Menche, S. Hippenmeyer, G. Novarino, Cell 186 (2023) 1950–1967.e25.","ieee":"L. Knaus et al., “Large neutral amino acid levels tune perinatal neuronal excitability and survival,” Cell, vol. 186, no. 9. Elsevier, p. 1950–1967.e25, 2023.","chicago":"Knaus, Lisa, Bernadette Basilico, Daniel Malzl, Maria Gerykova Bujalkova, Mateja Smogavec, Lena A. Schwarz, Sarah Gorkiewicz, et al. “Large Neutral Amino Acid Levels Tune Perinatal Neuronal Excitability and Survival.” Cell. Elsevier, 2023. https://doi.org/10.1016/j.cell.2023.02.037.","ista":"Knaus L, Basilico B, Malzl D, Gerykova Bujalkova M, Smogavec M, Schwarz LA, Gorkiewicz S, Amberg N, Pauler F, Knittl-Frank C, Tassinari M, Maulide N, Rülicke T, Menche J, Hippenmeyer S, Novarino G. 2023. Large neutral amino acid levels tune perinatal neuronal excitability and survival. Cell. 186(9), 1950–1967.e25."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","article_processing_charge":"Yes (via OA deal)","external_id":{"isi":["000991468700001"]},"author":[{"id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","first_name":"Lisa","full_name":"Knaus, Lisa","last_name":"Knaus"},{"id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette","full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173","last_name":"Basilico"},{"last_name":"Malzl","full_name":"Malzl, Daniel","first_name":"Daniel"},{"first_name":"Maria","full_name":"Gerykova Bujalkova, Maria","last_name":"Gerykova Bujalkova"},{"first_name":"Mateja","full_name":"Smogavec, Mateja","last_name":"Smogavec"},{"first_name":"Lena A.","full_name":"Schwarz, Lena A.","last_name":"Schwarz"},{"full_name":"Gorkiewicz, Sarah","last_name":"Gorkiewicz","first_name":"Sarah","id":"f141a35d-15a9-11ec-9fb2-fef6becc7b6f"},{"first_name":"Nicole","id":"4CD6AAC6-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0002-3183-8207","full_name":"Amberg, Nicole","last_name":"Amberg"},{"last_name":"Pauler","orcid":"0000-0002-7462-0048","full_name":"Pauler, Florian","id":"48EA0138-F248-11E8-B48F-1D18A9856A87","first_name":"Florian"},{"last_name":"Knittl-Frank","full_name":"Knittl-Frank, Christian","first_name":"Christian"},{"id":"7af593f1-d44a-11ed-bf94-a3646a6bb35e","first_name":"Marianna","last_name":"Tassinari","full_name":"Tassinari, Marianna"},{"first_name":"Nuno","full_name":"Maulide, Nuno","last_name":"Maulide"},{"last_name":"Rülicke","full_name":"Rülicke, Thomas","first_name":"Thomas"},{"full_name":"Menche, Jörg","last_name":"Menche","first_name":"Jörg"},{"id":"37B36620-F248-11E8-B48F-1D18A9856A87","first_name":"Simon","full_name":"Hippenmeyer, Simon","orcid":"0000-0003-2279-1061","last_name":"Hippenmeyer"},{"last_name":"Novarino","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178","id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia"}],"title":"Large neutral amino acid levels tune perinatal neuronal excitability and survival"},{"publication_status":"published","publication_identifier":{"issn":["1662-5102"]},"language":[{"iso":"eng"}],"file":[{"checksum":"84696213ecf99182c58a9f34b9ff2e23","file_id":"12352","success":1,"content_type":"application/pdf","access_level":"open_access","relation":"main_file","date_created":"2023-01-24T09:16:29Z","file_name":"2022_FrontiersNeuroscience_Basilico.pdf","date_updated":"2023-01-24T09:16:29Z","file_size":6399987,"creator":"dernst"}],"volume":16,"abstract":[{"text":"Microglia are dynamic cells, constantly surveying their surroundings and interacting with neurons and synapses. Indeed, a wealth of knowledge has revealed a critical role of microglia in modulating synaptic transmission and plasticity in the developing brain. In the past decade, novel pharmacological and genetic strategies have allowed the acute removal of microglia, opening the possibility to explore and understand the role of microglia also in the adult brain. In this review, we summarized and discussed the contribution of microglia depletion strategies to the current understanding of the role of microglia on synaptic function, learning and memory, and behavior both in physiological and pathological conditions. We first described the available microglia depletion methods highlighting their main strengths and weaknesses. We then reviewed the impact of microglia depletion on structural and functional synaptic plasticity. Next, we focused our analysis on the effects of microglia depletion on behavior, including general locomotor activity, sensory perception, motor function, sociability, learning and memory both in healthy animals and animal models of disease. Finally, we integrated the findings from the reviewed studies and discussed the emerging roles of microglia on the maintenance of synaptic function, learning, memory strength and forgetfulness, and the implications of microglia depletion in models of brain disease.","lang":"eng"}],"pmid":1,"oa_version":"Published Version","scopus_import":"1","intvolume":" 16","month":"11","date_updated":"2023-08-04T08:56:10Z","ddc":["570"],"department":[{"_id":"GaNo"}],"file_date_updated":"2023-01-24T09:16:29Z","_id":"12140","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","article_type":"original","keyword":["Cellular and Molecular Neuroscience"],"status":"public","year":"2022","has_accepted_license":"1","isi":1,"publication":"Frontiers in Cellular Neuroscience","day":"04","date_created":"2023-01-12T12:04:50Z","doi":"10.3389/fncel.2022.1022431","date_published":"2022-11-04T00:00:00Z","acknowledgement":"The write-up of the review was supported by Sapienza University of Rome (Fondi di Ateneo, grant numbers #MA32117A7B698029 and #PH12017270934C3C to SD), Regione Lazio (POR FSE 2014/20, grant number #19036AP000000019 to SD), Fulbright 2019 (grant number\r\n#FSP-P005556 to SD), Institute Pasteur Italia (Fondi Cenci Bolognetti #363 to DR), and Network of European Funding for Neuroscience Research (ERA-NET NEURON Transnational\r\nResearch Projects on Neurodevelopmental Disorders 2021, grant acronym #JTC2021-SHANKAstro to DR).","oa":1,"publisher":"Frontiers Media","quality_controlled":"1","citation":{"chicago":"Basilico, Bernadette, Laura Ferrucci, Azka Khan, Silvia Di Angelantonio, Davide Ragozzino, and Ingrid Reverte. “What Microglia Depletion Approaches Tell Us about the Role of Microglia on Synaptic Function and Behavior.” Frontiers in Cellular Neuroscience. Frontiers Media, 2022. https://doi.org/10.3389/fncel.2022.1022431.","ista":"Basilico B, Ferrucci L, Khan A, Di Angelantonio S, Ragozzino D, Reverte I. 2022. What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior. Frontiers in Cellular Neuroscience. 16, 1022431.","mla":"Basilico, Bernadette, et al. “What Microglia Depletion Approaches Tell Us about the Role of Microglia on Synaptic Function and Behavior.” Frontiers in Cellular Neuroscience, vol. 16, 1022431, Frontiers Media, 2022, doi:10.3389/fncel.2022.1022431.","ama":"Basilico B, Ferrucci L, Khan A, Di Angelantonio S, Ragozzino D, Reverte I. What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior. Frontiers in Cellular Neuroscience. 2022;16. doi:10.3389/fncel.2022.1022431","apa":"Basilico, B., Ferrucci, L., Khan, A., Di Angelantonio, S., Ragozzino, D., & Reverte, I. (2022). What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior. Frontiers in Cellular Neuroscience. Frontiers Media. https://doi.org/10.3389/fncel.2022.1022431","ieee":"B. Basilico, L. Ferrucci, A. Khan, S. Di Angelantonio, D. Ragozzino, and I. Reverte, “What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior,” Frontiers in Cellular Neuroscience, vol. 16. Frontiers Media, 2022.","short":"B. Basilico, L. Ferrucci, A. Khan, S. Di Angelantonio, D. Ragozzino, I. Reverte, Frontiers in Cellular Neuroscience 16 (2022)."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","external_id":{"isi":["000886526600001"],"pmid":["36406752"]},"article_processing_charge":"No","author":[{"first_name":"Bernadette","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","last_name":"Basilico","orcid":"0000-0003-1843-3173","full_name":"Basilico, Bernadette"},{"first_name":"Laura","last_name":"Ferrucci","full_name":"Ferrucci, Laura"},{"last_name":"Khan","full_name":"Khan, Azka","first_name":"Azka"},{"first_name":"Silvia","last_name":"Di Angelantonio","full_name":"Di Angelantonio, Silvia"},{"full_name":"Ragozzino, Davide","last_name":"Ragozzino","first_name":"Davide"},{"full_name":"Reverte, Ingrid","last_name":"Reverte","first_name":"Ingrid"}],"title":"What microglia depletion approaches tell us about the role of microglia on synaptic function and behavior","article_number":"1022431"},{"citation":{"ista":"Basilico B, Palamà IE, D’Amone S, Lauro C, Rosito M, Grieco M, Ratano P, Cordella F, Sanchini C, Di Angelantonio S, Ragozzino D, Cascione M, Gigli G, Cortese B. 2022. Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells. Frontiers in Oncology. 12, 983507.","chicago":"Basilico, Bernadette, Ilaria Elena Palamà, Stefania D’Amone, Clotilde Lauro, Maria Rosito, Maddalena Grieco, Patrizia Ratano, et al. “Substrate Stiffness Effect on Molecular Crosstalk of Epithelial-Mesenchymal Transition Mediators of Human Glioblastoma Cells.” Frontiers in Oncology. Frontiers Media, 2022. https://doi.org/10.3389/fonc.2022.983507.","ieee":"B. Basilico et al., “Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells,” Frontiers in Oncology, vol. 12. Frontiers Media, 2022.","short":"B. Basilico, I.E. Palamà, S. D’Amone, C. Lauro, M. Rosito, M. Grieco, P. Ratano, F. Cordella, C. Sanchini, S. Di Angelantonio, D. Ragozzino, M. Cascione, G. Gigli, B. Cortese, Frontiers in Oncology 12 (2022).","ama":"Basilico B, Palamà IE, D’Amone S, et al. Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells. Frontiers in Oncology. 2022;12. doi:10.3389/fonc.2022.983507","apa":"Basilico, B., Palamà, I. E., D’Amone, S., Lauro, C., Rosito, M., Grieco, M., … Cortese, B. (2022). Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells. Frontiers in Oncology. Frontiers Media. https://doi.org/10.3389/fonc.2022.983507","mla":"Basilico, Bernadette, et al. “Substrate Stiffness Effect on Molecular Crosstalk of Epithelial-Mesenchymal Transition Mediators of Human Glioblastoma Cells.” Frontiers in Oncology, vol. 12, 983507, Frontiers Media, 2022, doi:10.3389/fonc.2022.983507."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","article_processing_charge":"No","external_id":{"isi":["000856524900001"],"pmid":["36091138"]},"author":[{"first_name":"Bernadette","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173","last_name":"Basilico"},{"first_name":"Ilaria Elena","full_name":"Palamà, Ilaria Elena","last_name":"Palamà"},{"full_name":"D’Amone, Stefania","last_name":"D’Amone","first_name":"Stefania"},{"first_name":"Clotilde","last_name":"Lauro","full_name":"Lauro, Clotilde"},{"full_name":"Rosito, Maria","last_name":"Rosito","first_name":"Maria"},{"first_name":"Maddalena","last_name":"Grieco","full_name":"Grieco, Maddalena"},{"first_name":"Patrizia","full_name":"Ratano, Patrizia","last_name":"Ratano"},{"first_name":"Federica","full_name":"Cordella, Federica","last_name":"Cordella"},{"last_name":"Sanchini","full_name":"Sanchini, Caterina","first_name":"Caterina"},{"first_name":"Silvia","last_name":"Di Angelantonio","full_name":"Di Angelantonio, Silvia"},{"full_name":"Ragozzino, Davide","last_name":"Ragozzino","first_name":"Davide"},{"first_name":"Mariafrancesca","full_name":"Cascione, Mariafrancesca","last_name":"Cascione"},{"first_name":"Giuseppe","full_name":"Gigli, Giuseppe","last_name":"Gigli"},{"full_name":"Cortese, Barbara","last_name":"Cortese","first_name":"Barbara"}],"title":"Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells","article_number":"983507","year":"2022","has_accepted_license":"1","isi":1,"publication":"Frontiers in Oncology","day":"25","date_created":"2023-01-16T10:00:28Z","date_published":"2022-08-25T00:00:00Z","doi":"10.3389/fonc.2022.983507","acknowledgement":"The research leading to these results has received funding from AIRC under IG 2021 - ID. 26328 project – P.I. Cortese Barbara and AIRC under MFAG 2015 - ID. 16803 project – “P.I. Cortese Barbara”. The authors are also grateful to the ”Tecnopolo per la medicina di precisione” (TecnoMed Puglia) - Regione Puglia: DGR n.2117 del 21/11/2018, CUP: B84I18000540002 and “Tecnopolo di Nanotecnologia e Fotonica per la medicina di precisione” (TECNOMED) - FISR/MIUR-CNR: delibera CIPE n.3449 del 7-08-2017, CUP: B83B17000010001.\r\nWe thank Dr. Francesca Pagani for useful technical support. We thank also Irene Iacuitto, Giovanna Loffredo and Manuela Marchetti for practical administrative support.","oa":1,"publisher":"Frontiers Media","quality_controlled":"1","date_updated":"2023-08-04T09:54:16Z","ddc":["570"],"department":[{"_id":"GaNo"}],"file_date_updated":"2023-01-30T10:25:21Z","_id":"12268","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"type":"journal_article","article_type":"original","keyword":["Cancer Research","Oncology"],"status":"public","publication_status":"published","publication_identifier":{"issn":["2234-943X"]},"language":[{"iso":"eng"}],"file":[{"creator":"dernst","file_size":13588502,"date_updated":"2023-01-30T10:25:21Z","file_name":"2022_FrontiersOntology_Basilico.pdf","date_created":"2023-01-30T10:25:21Z","relation":"main_file","access_level":"open_access","content_type":"application/pdf","success":1,"file_id":"12450","checksum":"efc7edf9f626af31853790c5b598a68c"}],"volume":12,"abstract":[{"lang":"eng","text":"The complexity of the microenvironment effects on cell response, show accumulating evidence that glioblastoma (GBM) migration and invasiveness are influenced by the mechanical rigidity of their surroundings. The epithelial–mesenchymal transition (EMT) is a well-recognized driving force of the invasive behavior of cancer. However, the primary mechanisms of EMT initiation and progression remain unclear. We have previously showed that certain substrate stiffness can selectively stimulate human GBM U251-MG and GL15 glioblastoma cell lines motility. The present study unifies several known EMT mediators to uncover the reason of the regulation and response to these stiffnesses. Our results revealed that changing the rigidity of the mechanical environment tuned the response of both cell lines through change in morphological features, epithelial-mesenchymal markers (E-, N-Cadherin), EGFR and ROS expressions in an interrelated manner. Specifically, a stiffer microenvironment induced a mesenchymal cell shape, a more fragmented morphology, higher intracellular cytosolic ROS expression and lower mitochondrial ROS. Finally, we observed that cells more motile showed a more depolarized mitochondrial membrane potential. Unravelling the process that regulates GBM cells’ infiltrative behavior could provide new opportunities for identification of new targets and less invasive approaches for treatment."}],"oa_version":"Published Version","pmid":1,"scopus_import":"1","intvolume":" 12","month":"08"},{"volume":70,"issue":"1","file":[{"date_updated":"2022-03-04T08:55:27Z","file_size":5340294,"creator":"dernst","date_created":"2022-03-04T08:55:27Z","file_name":"2021_Glia_Basilico.pdf","content_type":"application/pdf","access_level":"open_access","relation":"main_file","file_id":"10819","checksum":"f10a897290e66c0a062e04ba91db6c17","success":1}],"language":[{"iso":"eng"}],"publication_identifier":{"issn":["0894-1491"],"eissn":["1098-1136"]},"publication_status":"published","month":"01","intvolume":" 70","scopus_import":"1","pmid":1,"oa_version":"Published Version","abstract":[{"lang":"eng","text":"Microglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence ofneuroinflammatory condition. PLX-induced synaptic changes were absent in Cx3cr1−/− mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in organization and activity of glutamatergic synapses."}],"file_date_updated":"2022-03-04T08:55:27Z","department":[{"_id":"GaNo"}],"ddc":["570"],"date_updated":"2023-09-05T16:01:23Z","status":"public","keyword":["Cellular and Molecular Neuroscience","Neurology"],"article_type":"original","type":"journal_article","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc/4.0/legalcode","image":"/images/cc_by_nc.png","name":"Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)","short":"CC BY-NC (4.0)"},"_id":"10818","doi":"10.1002/glia.24101","date_published":"2022-01-01T00:00:00Z","date_created":"2022-03-04T08:53:37Z","page":"173-195","day":"01","publication":"Glia","has_accepted_license":"1","isi":1,"year":"2022","quality_controlled":"1","publisher":"Wiley","oa":1,"acknowledgement":"The work was supported by a grant from MIUR (PRIN 2017HPTFFC_003) to Davide Ragozzino and in part by funds to Silvia Di Angelantonio (CrestOptics-IIT JointLab for Advanced Microscopy) and Daniele Caprioli (Istituto Pasteur-Fondazione Cenci Bolognetti). Bernadette Basilico, and Laura Ferrucci were supported by the PhD program in Clinical-Experimental Neuroscience and Psychiatry, Sapienza University, Rome; Caterina Sanchini was supported by the PhD program in Life Science, Sapienza University, Rome and by the Italian Institute of Technology, Rome. The authors thank Alessandro Felici, Claudia Valeri, Arsenio Armagno, and Senthilkumar Deivasigamani for help with animal husbandry and transgenic colonies management. They also wish to thank Piotr Bregestovski and Michal Schwartz for helpful discussions and criticism. PLX5622 was provided under Materials Transfer Agreement by Plexxikon Inc. (Berkeley, CA). Open Access Funding provided by Universita degli Studi di Roma La Sapienza within the CRUI-CARE Agreement.","title":"Microglia control glutamatergic synapses in the adult mouse hippocampus","author":[{"full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173","last_name":"Basilico","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette"},{"last_name":"Ferrucci","full_name":"Ferrucci, Laura","first_name":"Laura"},{"last_name":"Ratano","full_name":"Ratano, Patrizia","first_name":"Patrizia"},{"full_name":"Golia, Maria T.","last_name":"Golia","first_name":"Maria T."},{"first_name":"Alfonso","last_name":"Grimaldi","full_name":"Grimaldi, Alfonso"},{"first_name":"Maria","full_name":"Rosito, Maria","last_name":"Rosito"},{"full_name":"Ferretti, Valentina","last_name":"Ferretti","first_name":"Valentina"},{"first_name":"Ingrid","last_name":"Reverte","full_name":"Reverte, Ingrid"},{"last_name":"Sanchini","full_name":"Sanchini, Caterina","first_name":"Caterina"},{"last_name":"Marrone","full_name":"Marrone, Maria C.","first_name":"Maria C."},{"last_name":"Giubettini","full_name":"Giubettini, Maria","first_name":"Maria"},{"last_name":"De Turris","full_name":"De Turris, Valeria","first_name":"Valeria"},{"first_name":"Debora","last_name":"Salerno","full_name":"Salerno, Debora"},{"first_name":"Stefano","last_name":"Garofalo","full_name":"Garofalo, Stefano"},{"full_name":"St‐Pierre, Marie‐Kim","last_name":"St‐Pierre","first_name":"Marie‐Kim"},{"first_name":"Micael","full_name":"Carrier, Micael","last_name":"Carrier"},{"last_name":"Renzi","full_name":"Renzi, Massimiliano","first_name":"Massimiliano"},{"first_name":"Francesca","full_name":"Pagani, Francesca","last_name":"Pagani"},{"full_name":"Modi, Brijesh","last_name":"Modi","first_name":"Brijesh"},{"full_name":"Raspa, Marcello","last_name":"Raspa","first_name":"Marcello"},{"full_name":"Scavizzi, Ferdinando","last_name":"Scavizzi","first_name":"Ferdinando"},{"first_name":"Cornelius T.","last_name":"Gross","full_name":"Gross, Cornelius T."},{"last_name":"Marinelli","full_name":"Marinelli, Silvia","first_name":"Silvia"},{"last_name":"Tremblay","full_name":"Tremblay, Marie‐Ève","first_name":"Marie‐Ève"},{"last_name":"Caprioli","full_name":"Caprioli, Daniele","first_name":"Daniele"},{"first_name":"Laura","last_name":"Maggi","full_name":"Maggi, Laura"},{"first_name":"Cristina","full_name":"Limatola, Cristina","last_name":"Limatola"},{"first_name":"Silvia","full_name":"Di Angelantonio, Silvia","last_name":"Di Angelantonio"},{"first_name":"Davide","last_name":"Ragozzino","full_name":"Ragozzino, Davide"}],"article_processing_charge":"No","external_id":{"isi":["000708025800001"],"pmid":["34661306"]},"user_id":"c635000d-4b10-11ee-a964-aac5a93f6ac1","citation":{"mla":"Basilico, Bernadette, et al. “Microglia Control Glutamatergic Synapses in the Adult Mouse Hippocampus.” Glia, vol. 70, no. 1, Wiley, 2022, pp. 173–95, doi:10.1002/glia.24101.","apa":"Basilico, B., Ferrucci, L., Ratano, P., Golia, M. T., Grimaldi, A., Rosito, M., … Ragozzino, D. (2022). Microglia control glutamatergic synapses in the adult mouse hippocampus. Glia. Wiley. https://doi.org/10.1002/glia.24101","ama":"Basilico B, Ferrucci L, Ratano P, et al. Microglia control glutamatergic synapses in the adult mouse hippocampus. Glia. 2022;70(1):173-195. doi:10.1002/glia.24101","short":"B. Basilico, L. Ferrucci, P. Ratano, M.T. Golia, A. Grimaldi, M. Rosito, V. Ferretti, I. Reverte, C. Sanchini, M.C. Marrone, M. Giubettini, V. De Turris, D. Salerno, S. Garofalo, M. St‐Pierre, M. Carrier, M. Renzi, F. Pagani, B. Modi, M. Raspa, F. Scavizzi, C.T. Gross, S. Marinelli, M. Tremblay, D. Caprioli, L. Maggi, C. Limatola, S. Di Angelantonio, D. Ragozzino, Glia 70 (2022) 173–195.","ieee":"B. Basilico et al., “Microglia control glutamatergic synapses in the adult mouse hippocampus,” Glia, vol. 70, no. 1. Wiley, pp. 173–195, 2022.","chicago":"Basilico, Bernadette, Laura Ferrucci, Patrizia Ratano, Maria T. Golia, Alfonso Grimaldi, Maria Rosito, Valentina Ferretti, et al. “Microglia Control Glutamatergic Synapses in the Adult Mouse Hippocampus.” Glia. Wiley, 2022. https://doi.org/10.1002/glia.24101.","ista":"Basilico B, Ferrucci L, Ratano P, Golia MT, Grimaldi A, Rosito M, Ferretti V, Reverte I, Sanchini C, Marrone MC, Giubettini M, De Turris V, Salerno D, Garofalo S, St‐Pierre M, Carrier M, Renzi M, Pagani F, Modi B, Raspa M, Scavizzi F, Gross CT, Marinelli S, Tremblay M, Caprioli D, Maggi L, Limatola C, Di Angelantonio S, Ragozzino D. 2022. Microglia control glutamatergic synapses in the adult mouse hippocampus. Glia. 70(1), 173–195."}},{"date_updated":"2023-10-03T09:49:18Z","department":[{"_id":"GaNo"}],"_id":"9953","status":"public","article_type":"original","type":"journal_article","language":[{"iso":"eng"}],"publication_status":"published","publication_identifier":{"issn":["0889-1591"]},"volume":97,"oa_version":"Submitted Version","pmid":1,"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."}],"intvolume":" 97","month":"10","main_file_link":[{"open_access":"1","url":"https://www.zora.uzh.ch/id/eprint/208855/1/ZORA208855.pdf"}],"scopus_import":"1","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","citation":{"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.","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","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","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.","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.","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.","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."},"title":"Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice","article_processing_charge":"No","external_id":{"isi":["000702878400007"],"pmid":["34343616"]},"author":[{"full_name":"Picard, Katherine","last_name":"Picard","first_name":"Katherine"},{"full_name":"Bisht, Kanchan","last_name":"Bisht","first_name":"Kanchan"},{"first_name":"Silvia","last_name":"Poggini","full_name":"Poggini, Silvia"},{"full_name":"Garofalo, Stefano","last_name":"Garofalo","first_name":"Stefano"},{"first_name":"Maria Teresa","full_name":"Golia, Maria Teresa","last_name":"Golia"},{"first_name":"Bernadette","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173","last_name":"Basilico"},{"last_name":"Abdallah","full_name":"Abdallah, Fatima","first_name":"Fatima"},{"full_name":"Ciano Albanese, Naomi","last_name":"Ciano Albanese","first_name":"Naomi"},{"first_name":"Irmgard","last_name":"Amrein","full_name":"Amrein, Irmgard"},{"last_name":"Vernoux","full_name":"Vernoux, Nathalie","first_name":"Nathalie"},{"first_name":"Kaushik","full_name":"Sharma, Kaushik","last_name":"Sharma"},{"full_name":"Hui, Chin Wai","last_name":"Hui","first_name":"Chin Wai"},{"first_name":"Julie","last_name":"C. Savage","full_name":"C. Savage, Julie"},{"first_name":"Cristina","last_name":"Limatola","full_name":"Limatola, Cristina"},{"last_name":"Ragozzino","full_name":"Ragozzino, Davide","first_name":"Davide"},{"first_name":"Laura","full_name":"Maggi, Laura","last_name":"Maggi"},{"full_name":"Branchi, Igor","last_name":"Branchi","first_name":"Igor"},{"first_name":"Marie Ève","full_name":"Tremblay, Marie Ève","last_name":"Tremblay"}],"publication":"Brain, Behavior, and Immunity","day":"01","year":"2021","isi":1,"date_created":"2021-08-22T22:01:21Z","date_published":"2021-10-01T00:00:00Z","doi":"10.1016/j.bbi.2021.07.022","page":"423-439","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.","oa":1,"publisher":"Elsevier","quality_controlled":"1"},{"citation":{"mla":"Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” Nature Communications, vol. 12, no. 1, 3058, Springer Nature, 2021, doi:10.1038/s41467-021-23123-x.","ieee":"J. Morandell et al., “Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development,” Nature Communications, vol. 12, no. 1. Springer Nature, 2021.","short":"J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, G.A. Dimchev, A. Nicolas, C.M. Sommer, C. Kreuzinger, C. Dotter, L. Knaus, Z. Dobler, E. Cacci, F.K. Schur, J.G. Danzl, G. Novarino, Nature Communications 12 (2021).","apa":"Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Dimchev, G. A., Nicolas, A., … Novarino, G. (2021). Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. Springer Nature. https://doi.org/10.1038/s41467-021-23123-x","ama":"Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. 2021;12(1). doi:10.1038/s41467-021-23123-x","chicago":"Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan, Georgi A Dimchev, Armel Nicolas, Christoph M Sommer, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” Nature Communications. Springer Nature, 2021. https://doi.org/10.1038/s41467-021-23123-x.","ista":"Morandell J, Schwarz LA, Basilico B, Tasciyan S, Dimchev GA, Nicolas A, Sommer CM, Kreuzinger C, Dotter C, Knaus L, Dobler Z, Cacci E, Schur FK, Danzl JG, Novarino G. 2021. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nature Communications. 12(1), 3058."},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","author":[{"id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin","full_name":"Morandell, Jasmin","last_name":"Morandell"},{"last_name":"Schwarz","full_name":"Schwarz, Lena A","id":"29A8453C-F248-11E8-B48F-1D18A9856A87","first_name":"Lena A"},{"id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette","orcid":"0000-0003-1843-3173","full_name":"Basilico, Bernadette","last_name":"Basilico"},{"id":"4323B49C-F248-11E8-B48F-1D18A9856A87","first_name":"Saren","orcid":"0000-0003-1671-393X","full_name":"Tasciyan, Saren","last_name":"Tasciyan"},{"last_name":"Dimchev","orcid":"0000-0001-8370-6161","full_name":"Dimchev, Georgi A","id":"38C393BE-F248-11E8-B48F-1D18A9856A87","first_name":"Georgi A"},{"full_name":"Nicolas, Armel","last_name":"Nicolas","first_name":"Armel","id":"2A103192-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Sommer, Christoph M","orcid":"0000-0003-1216-9105","last_name":"Sommer","first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Kreuzinger, Caroline","last_name":"Kreuzinger","id":"382077BA-F248-11E8-B48F-1D18A9856A87","first_name":"Caroline"},{"last_name":"Dotter","full_name":"Dotter, Christoph","orcid":"0000-0002-9033-9096","first_name":"Christoph","id":"4C66542E-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Knaus, Lisa","last_name":"Knaus","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87","first_name":"Lisa"},{"id":"D23090A2-9057-11EA-883A-A8396FC7A38F","first_name":"Zoe","full_name":"Dobler, Zoe","last_name":"Dobler"},{"last_name":"Cacci","full_name":"Cacci, Emanuele","first_name":"Emanuele"},{"first_name":"Florian KM","id":"48AD8942-F248-11E8-B48F-1D18A9856A87","full_name":"Schur, Florian KM","orcid":"0000-0003-4790-8078","last_name":"Schur"},{"last_name":"Danzl","full_name":"Danzl, Johann G","orcid":"0000-0001-8559-3973","first_name":"Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87"},{"orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia","last_name":"Novarino","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"}],"external_id":{"isi":["000658769900010"]},"article_processing_charge":"No","title":"Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development","article_number":"3058","project":[{"_id":"260C2330-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","name":"ISTplus - Postdoctoral Fellowships","grant_number":"754411"},{"_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","grant_number":"715508"},{"_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Molecular Drug Targets","grant_number":"W1232-B24"},{"_id":"05A0D778-7A3F-11EA-A408-12923DDC885E","grant_number":"F07807","name":"Neural stem cells in autism and epilepsy"},{"_id":"265CB4D0-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","grant_number":"I03600","name":"Optical control of synaptic function via adhesion molecules"}],"has_accepted_license":"1","isi":1,"year":"2021","day":"24","publication":"Nature Communications","date_published":"2021-05-24T00:00:00Z","doi":"10.1038/s41467-021-23123-x","date_created":"2021-05-28T11:49:46Z","acknowledgement":"We thank A. Coll Manzano, F. Freeman, M. Ladron de Guevara, and A. Ç. Yahya for technical assistance, S. Deixler, A. Lepold, and A. Schlerka for the management of our animal colony, as well as M. Schunn and the Preclinical Facility team for technical assistance. We thank K. Heesom and her team at the University of Bristol Proteomics Facility for the proteomics sample preparation, data generation, and analysis support. We thank Y. B. Simon for kindly providing the plasmid for lentiviral labeling. Further, we thank M. Sixt for his advice regarding cell migration and the fruitful discussions. This work was supported by the ISTPlus postdoctoral fellowship (Grant Agreement No. 754411) to B.B., by the European Union’s Horizon 2020 research and innovation program (ERC) grant 715508 (REVERSEAUTISM), and by the Austrian Science Fund (FWF) to G.N. (DK W1232-B24 and SFB F7807-B) and to J.G.D (I3600-B27).","publisher":"Springer Nature","quality_controlled":"1","oa":1,"date_updated":"2024-03-27T23:30:23Z","ddc":["572"],"file_date_updated":"2021-05-28T12:39:43Z","department":[{"_id":"GaNo"},{"_id":"JoDa"},{"_id":"FlSc"},{"_id":"MiSi"},{"_id":"LifeSc"},{"_id":"Bio"}],"_id":"9429","type":"journal_article","article_type":"original","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)"},"status":"public","keyword":["General Biochemistry","Genetics and Molecular Biology"],"publication_identifier":{"eissn":["2041-1723"]},"publication_status":"published","file":[{"file_id":"9430","checksum":"337e0f7959c35ec959984cacdcb472ba","success":1,"access_level":"open_access","relation":"main_file","content_type":"application/pdf","date_created":"2021-05-28T12:39:43Z","file_name":"2021_NatureCommunications_Morandell.pdf","creator":"kschuh","date_updated":"2021-05-28T12:39:43Z","file_size":9358599}],"language":[{"iso":"eng"}],"volume":12,"related_material":{"record":[{"relation":"earlier_version","status":"public","id":"7800"},{"relation":"dissertation_contains","status":"public","id":"12401"}],"link":[{"url":"https://ist.ac.at/en/news/defective-gene-slows-down-brain-cells/","relation":"press_release"}]},"issue":"1","ec_funded":1,"abstract":[{"text":"De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 lead to autism spectrum disorder (ASD). In mouse, constitutive haploinsufficiency leads to motor coordination deficits as well as ASD-relevant social and cognitive impairments. However, induction of Cul3 haploinsufficiency later in life does not lead to ASD-relevant behaviors, pointing to an important role of Cul3 during a critical developmental window. Here we show that Cul3 is essential to regulate neuronal migration and, therefore, constitutive Cul3 heterozygous mutant mice display cortical lamination abnormalities. At the molecular level, we found that Cul3 controls neuronal migration by tightly regulating the amount of Plastin3 (Pls3), a previously unrecognized player of neural migration. Furthermore, we found that Pls3 cell-autonomously regulates cell migration by regulating actin cytoskeleton organization, and its levels are inversely proportional to neural migration speed. Finally, we provide evidence that cellular phenotypes associated with autism-linked gene haploinsufficiency can be rescued by transcriptional activation of the intact allele in vitro, offering a proof of concept for a potential therapeutic approach for ASDs.","lang":"eng"}],"acknowledged_ssus":[{"_id":"PreCl"}],"oa_version":"Published Version","month":"05","intvolume":" 12"},{"_id":"7800","tmp":{"short":"CC BY-NC-ND (4.0)","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png"},"type":"preprint","status":"public","date_updated":"2024-03-27T23:30:14Z","ddc":["570"],"department":[{"_id":"JoDa"},{"_id":"GaNo"},{"_id":"LifeSc"}],"file_date_updated":"2020-07-14T12:48:03Z","abstract":[{"text":"De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). Here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 haploinsufficient mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3 mutant brain displays cortical lamination abnormalities due to defective neuronal migration and reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal columnar organization, Cul3 haploinsufficiency is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative proteomic approach, we show that Cul3 regulates cytoskeletal and adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neuronal cells results in atypical organization of the actin mesh at the cell leading edge, likely causing the observed migration deficits. In contrast to these important functions early in development, Cul3 deficiency appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency in adult mice does not result in the behavioral defects observed in constitutive Cul3 haploinsufficient animals. Taken together, our data indicate that Cul3 has a critical role in the regulation of cytoskeletal proteins and neuronal migration and that ASD-associated defects and behavioral abnormalities are primarily due to Cul3 functions at early developmental stages.","lang":"eng"}],"acknowledged_ssus":[{"_id":"PreCl"}],"oa_version":"Preprint","month":"01","publication_status":"submitted","language":[{"iso":"eng"}],"file":[{"checksum":"c6799ab5daba80efe8e2ed63c15f8c81","file_id":"7801","content_type":"application/pdf","access_level":"open_access","relation":"main_file","date_created":"2020-05-05T14:31:19Z","file_name":"2020.01.10.902064v1.full.pdf","date_updated":"2020-07-14T12:48:03Z","file_size":2931370,"creator":"rsix"}],"related_material":{"record":[{"relation":"later_version","id":"9429","status":"public"},{"relation":"dissertation_contains","id":"8620","status":"public"}]},"project":[{"name":"Optical control of synaptic function via adhesion molecules","grant_number":"I03600","_id":"265CB4D0-B435-11E9-9278-68D0E5697425","call_identifier":"FWF"},{"_id":"2548AE96-B435-11E9-9278-68D0E5697425","call_identifier":"FWF","name":"Molecular Drug Targets","grant_number":"W1232-B24"}],"citation":{"ista":"Morandell J, Schwarz LA, Basilico B, Tasciyan S, Nicolas A, Sommer CM, Kreuzinger C, Knaus L, Dobler Z, Cacci E, Danzl JG, Novarino G. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv, 10.1101/2020.01.10.902064 .","chicago":"Morandell, Jasmin, Lena A Schwarz, Bernadette Basilico, Saren Tasciyan, Armel Nicolas, Christoph M Sommer, Caroline Kreuzinger, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” BioRxiv. Cold Spring Harbor Laboratory, n.d. https://doi.org/10.1101/2020.01.10.902064 .","apa":"Morandell, J., Schwarz, L. A., Basilico, B., Tasciyan, S., Nicolas, A., Sommer, C. M., … Novarino, G. (n.d.). Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2020.01.10.902064 ","ama":"Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. bioRxiv. doi:10.1101/2020.01.10.902064 ","short":"J. Morandell, L.A. Schwarz, B. Basilico, S. Tasciyan, A. Nicolas, C.M. Sommer, C. Kreuzinger, L. Knaus, Z. Dobler, E. Cacci, J.G. Danzl, G. Novarino, BioRxiv (n.d.).","ieee":"J. Morandell et al., “Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development,” bioRxiv. Cold Spring Harbor Laboratory.","mla":"Morandell, Jasmin, et al. “Cul3 Regulates Cytoskeleton Protein Homeostasis and Cell Migration during a Critical Window of Brain Development.” BioRxiv, Cold Spring Harbor Laboratory, doi:10.1101/2020.01.10.902064 ."},"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","article_processing_charge":"No","author":[{"id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin","last_name":"Morandell","full_name":"Morandell, Jasmin"},{"id":"29A8453C-F248-11E8-B48F-1D18A9856A87","first_name":"Lena A","full_name":"Schwarz, Lena A","last_name":"Schwarz"},{"id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette","full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173","last_name":"Basilico"},{"first_name":"Saren","id":"4323B49C-F248-11E8-B48F-1D18A9856A87","last_name":"Tasciyan","full_name":"Tasciyan, Saren","orcid":"0000-0003-1671-393X"},{"id":"2A103192-F248-11E8-B48F-1D18A9856A87","first_name":"Armel","full_name":"Nicolas, Armel","last_name":"Nicolas"},{"first_name":"Christoph M","id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","full_name":"Sommer, Christoph M","orcid":"0000-0003-1216-9105","last_name":"Sommer"},{"first_name":"Caroline","id":"382077BA-F248-11E8-B48F-1D18A9856A87","full_name":"Kreuzinger, Caroline","last_name":"Kreuzinger"},{"last_name":"Knaus","full_name":"Knaus, Lisa","first_name":"Lisa","id":"3B2ABCF4-F248-11E8-B48F-1D18A9856A87"},{"full_name":"Dobler, Zoe","last_name":"Dobler","first_name":"Zoe","id":"D23090A2-9057-11EA-883A-A8396FC7A38F"},{"first_name":"Emanuele","last_name":"Cacci","full_name":"Cacci, Emanuele"},{"first_name":"Johann G","id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","last_name":"Danzl","full_name":"Danzl, Johann G","orcid":"0000-0001-8559-3973"},{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","first_name":"Gaia","last_name":"Novarino","orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia"}],"title":"Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development","oa":1,"publisher":"Cold Spring Harbor Laboratory","year":"2020","has_accepted_license":"1","publication":"bioRxiv","day":"11","date_created":"2020-05-05T14:31:33Z","date_published":"2020-01-11T00:00:00Z","doi":"10.1101/2020.01.10.902064 "},{"title":"Molecular mechanisms for targeted ASD treatments","author":[{"full_name":"Basilico, Bernadette","orcid":"0000-0003-1843-3173","last_name":"Basilico","id":"36035796-5ACA-11E9-A75E-7AF2E5697425","first_name":"Bernadette"},{"id":"4739D480-F248-11E8-B48F-1D18A9856A87","first_name":"Jasmin","full_name":"Morandell, Jasmin","last_name":"Morandell"},{"orcid":"0000-0002-7673-7178","full_name":"Novarino, Gaia","last_name":"Novarino","first_name":"Gaia","id":"3E57A680-F248-11E8-B48F-1D18A9856A87"}],"article_processing_charge":"Yes (via OA deal)","external_id":{"pmid":["32659636"],"isi":["000598918900019"]},"user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","citation":{"ista":"Basilico B, Morandell J, Novarino G. 2020. Molecular mechanisms for targeted ASD treatments. Current Opinion in Genetics and Development. 65(12), 126–137.","chicago":"Basilico, Bernadette, Jasmin Morandell, and Gaia Novarino. “Molecular Mechanisms for Targeted ASD Treatments.” Current Opinion in Genetics and Development. Elsevier, 2020. https://doi.org/10.1016/j.gde.2020.06.004.","ieee":"B. Basilico, J. Morandell, and G. Novarino, “Molecular mechanisms for targeted ASD treatments,” Current Opinion in Genetics and Development, vol. 65, no. 12. Elsevier, pp. 126–137, 2020.","short":"B. Basilico, J. Morandell, G. Novarino, Current Opinion in Genetics and Development 65 (2020) 126–137.","apa":"Basilico, B., Morandell, J., & Novarino, G. (2020). Molecular mechanisms for targeted ASD treatments. Current Opinion in Genetics and Development. Elsevier. https://doi.org/10.1016/j.gde.2020.06.004","ama":"Basilico B, Morandell J, Novarino G. Molecular mechanisms for targeted ASD treatments. Current Opinion in Genetics and Development. 2020;65(12):126-137. doi:10.1016/j.gde.2020.06.004","mla":"Basilico, Bernadette, et al. “Molecular Mechanisms for Targeted ASD Treatments.” Current Opinion in Genetics and Development, vol. 65, no. 12, Elsevier, 2020, pp. 126–37, doi:10.1016/j.gde.2020.06.004."},"project":[{"call_identifier":"H2020","_id":"260C2330-B435-11E9-9278-68D0E5697425","name":"ISTplus - Postdoctoral Fellowships","grant_number":"754411"},{"call_identifier":"FWF","_id":"2548AE96-B435-11E9-9278-68D0E5697425","name":"Molecular Drug Targets","grant_number":"W1232-B24"},{"grant_number":"F07807","name":"Neural stem cells in autism and epilepsy","_id":"05A0D778-7A3F-11EA-A408-12923DDC885E"}],"date_published":"2020-12-01T00:00:00Z","doi":"10.1016/j.gde.2020.06.004","date_created":"2020-07-19T22:00:58Z","page":"126-137","day":"01","publication":"Current Opinion in Genetics and Development","isi":1,"has_accepted_license":"1","year":"2020","quality_controlled":"1","publisher":"Elsevier","oa":1,"file_date_updated":"2020-07-22T06:47:45Z","department":[{"_id":"GaNo"}],"ddc":["570"],"date_updated":"2024-03-27T23:30:14Z","status":"public","article_type":"original","type":"journal_article","tmp":{"short":"CC BY-NC-ND (4.0)","name":"Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)","legal_code_url":"https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode","image":"/images/cc_by_nc_nd.png"},"_id":"8131","issue":"12","volume":65,"related_material":{"record":[{"status":"public","id":"8620","relation":"dissertation_contains"}]},"ec_funded":1,"file":[{"content_type":"application/pdf","access_level":"open_access","relation":"main_file","file_id":"8146","success":1,"date_updated":"2020-07-22T06:47:45Z","file_size":1381545,"creator":"dernst","date_created":"2020-07-22T06:47:45Z","file_name":"2020_CurrentOpGenetics_Basilico.pdf"}],"language":[{"iso":"eng"}],"publication_identifier":{"eissn":["18790380"],"issn":["0959437X"]},"publication_status":"published","month":"12","intvolume":" 65","scopus_import":"1","oa_version":"Published Version","pmid":1,"abstract":[{"text":"The possibility to generate construct valid animal models enabled the development and testing of therapeutic strategies targeting the core features of autism spectrum disorders (ASDs). At the same time, these studies highlighted the necessity of identifying sensitive developmental time windows for successful therapeutic interventions. Animal and human studies also uncovered the possibility to stratify the variety of ASDs in molecularly distinct subgroups, potentially facilitating effective treatment design. Here, we focus on the molecular pathways emerging as commonly affected by mutations in diverse ASD-risk genes, on their role during critical windows of brain development and the potential treatments targeting these biological processes.","lang":"eng"}]}]