--- _id: '12364' abstract: - lang: eng text: "Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders character\x02ized 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." alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Christoph full_name: Dotter, Christoph id: 4C66542E-F248-11E8-B48F-1D18A9856A87 last_name: Dotter orcid: 0000-0002-9033-9096 citation: ama: Dotter C. Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. 2022. doi:10.15479/at:ista:12094 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 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. ieee: C. Dotter, “Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder,” Institute of Science and Technology Austria, 2022. ista: Dotter C. 2022. Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. Institute of Science and Technology Austria. 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. short: C. Dotter, Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder, Institute of Science and Technology Austria, 2022. date_created: 2023-01-24T13:09:57Z date_published: 2022-09-19T00:00:00Z date_updated: 2023-11-16T13:10:22Z day: '19' ddc: - '570' degree_awarded: PhD department: - _id: GradSch - _id: GaNo doi: 10.15479/at:ista:12094 ec_funded: 1 file: - access_level: open_access checksum: 896f4cac9adb6d3f26a6605772f4e1a3 content_type: application/pdf creator: cchlebak date_created: 2023-01-24T13:15:45Z date_updated: 2023-09-20T22:30:03Z embargo: 2023-09-19 file_id: '12365' file_name: 220923_Thesis_CDotter_Final.pdf file_size: 20457465 relation: main_file - access_level: closed checksum: ad01bb20da163be6893b7af832e58419 content_type: application/x-zip-compressed creator: cchlebak date_created: 2023-02-02T09:15:35Z date_updated: 2023-09-20T22:30:03Z embargo_to: open_access file_id: '12482' file_name: latex_source_CDotter_Thesis_2022.zip file_size: 22433512 relation: source_file file_date_updated: 2023-09-20T22:30:03Z has_accepted_license: '1' language: - iso: eng month: '09' oa: 1 oa_version: Published Version page: '152' project: - _id: 254BA948-B435-11E9-9278-68D0E5697425 grant_number: '401299' name: Probing development and reversibility of autism spectrum disorders - _id: 9B91375C-BA93-11EA-9121-9846C619BF3A grant_number: '707964' name: Critical windows and reversibility of ASD associated with mutations in chromatin remodelers - _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 - _id: 2690FEAC-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: I04205 name: Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria related_material: record: - id: '3' relation: part_of_dissertation status: public - id: '11160' relation: part_of_dissertation status: public status: public supervisor: - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 title: Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder type: dissertation user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9 year: '2022' ... --- _id: '10281' 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 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.' alternative_title: - Special Issue "From Genes to Therapy in Autism Spectrum Disorder" article_number: '1746' article_processing_charge: No article_type: original author: - first_name: Verica full_name: Vasic, Verica last_name: Vasic - first_name: Mattson S.O. full_name: Jones, Mattson S.O. last_name: Jones - first_name: Denise full_name: Haslinger, Denise id: 76922BDA-3D3B-11EA-90BD-A44F3DDC885E last_name: Haslinger - first_name: Lisa full_name: Knaus, Lisa id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87 last_name: Knaus - first_name: Michael J. full_name: Schmeisser, Michael J. last_name: Schmeisser - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 - first_name: Andreas G. full_name: Chiocchetti, Andreas G. last_name: Chiocchetti citation: 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' 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' 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.' 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.' 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.' 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). date_created: 2021-11-14T23:01:24Z date_published: 2021-10-30T00:00:00Z date_updated: 2023-08-14T11:46:12Z day: '30' ddc: - '570' department: - _id: GaNo doi: 10.3390/genes12111746 ec_funded: 1 external_id: isi: - '000834044200002' file: - access_level: open_access checksum: 256cb832a9c3051c7dc741f6423b8cbd content_type: application/pdf creator: dernst date_created: 2022-05-16T07:02:27Z date_updated: 2022-05-16T07:02:27Z file_id: '11380' file_name: 2021_Genes_Vasic.pdf file_size: 1335308 relation: main_file success: 1 file_date_updated: 2022-05-16T07:02:27Z has_accepted_license: '1' intvolume: ' 12' isi: 1 issue: '11' language: - iso: eng month: '10' oa: 1 oa_version: Published Version project: - _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 - _id: 2548AE96-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: W1232-B24 name: Molecular Drug Targets publication: Genes publication_identifier: eissn: - 2073-4425 publication_status: published publisher: MDPI quality_controlled: '1' scopus_import: '1' status: public title: 'Translating the role of mtor-and ras-associated signalopathies in autism spectrum disorder: Models, mechanisms and treatment' tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 12 year: '2021' ... --- _id: '10301' 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. 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). article_number: e71575 article_processing_charge: No article_type: original author: - first_name: María J full_name: Conde-Dusman, María J last_name: Conde-Dusman - first_name: Partha N full_name: Dey, Partha N last_name: Dey - first_name: Óscar full_name: Elía-Zudaire, Óscar last_name: Elía-Zudaire - first_name: Luis E full_name: Garcia Rabaneda, Luis E id: 33D1B084-F248-11E8-B48F-1D18A9856A87 last_name: Garcia Rabaneda - first_name: Carmen full_name: García-Lira, Carmen last_name: García-Lira - first_name: Teddy full_name: Grand, Teddy last_name: Grand - first_name: Victor full_name: Briz, Victor last_name: Briz - first_name: Eric R full_name: Velasco, Eric R last_name: Velasco - first_name: Raül full_name: Andero Galí, Raül last_name: Andero Galí - first_name: Sergio full_name: Niñerola, Sergio last_name: Niñerola - first_name: Angel full_name: Barco, Angel last_name: Barco - first_name: Pierre full_name: Paoletti, Pierre last_name: Paoletti - first_name: John F full_name: Wesseling, John F last_name: Wesseling - first_name: Fabrizio full_name: Gardoni, Fabrizio last_name: Gardoni - first_name: Steven J full_name: Tavalin, Steven J last_name: Tavalin - first_name: Isabel full_name: Perez-Otaño, Isabel last_name: Perez-Otaño citation: 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 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. 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. 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. 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). date_created: 2021-11-18T06:59:45Z date_published: 2021-11-17T00:00:00Z date_updated: 2023-08-14T11:50:50Z day: '17' ddc: - '570' department: - _id: GaNo doi: 10.7554/elife.71575 external_id: isi: - '000720945900001' file: - access_level: open_access checksum: 59318e9e41507cec83c2f4070e6ad540 content_type: application/pdf creator: lgarciar date_created: 2021-11-18T07:02:02Z date_updated: 2021-11-18T07:02:02Z file_id: '10302' file_name: elife-71575-v1.pdf file_size: 2477302 relation: main_file success: 1 file_date_updated: 2021-11-18T07:02:02Z has_accepted_license: '1' intvolume: ' 10' isi: 1 keyword: - general immunology and microbiology - general biochemistry - genetics and molecular biology - general medicine - general neuroscience language: - iso: eng month: '11' oa: 1 oa_version: Published Version publication: eLife publication_identifier: issn: - 2050-084X publication_status: published publisher: eLife Sciences Publications quality_controlled: '1' status: public title: Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 4359f0d1-fa6c-11eb-b949-802e58b17ae8 volume: 10 year: '2021' ... --- _id: '9953' 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. 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. article_processing_charge: No article_type: original author: - first_name: Katherine full_name: Picard, Katherine last_name: Picard - first_name: Kanchan full_name: Bisht, Kanchan last_name: Bisht - first_name: Silvia full_name: Poggini, Silvia last_name: Poggini - first_name: Stefano full_name: Garofalo, Stefano last_name: Garofalo - first_name: Maria Teresa full_name: Golia, Maria Teresa last_name: Golia - first_name: Bernadette full_name: Basilico, Bernadette id: 36035796-5ACA-11E9-A75E-7AF2E5697425 last_name: Basilico orcid: 0000-0003-1843-3173 - first_name: Fatima full_name: Abdallah, Fatima last_name: Abdallah - first_name: Naomi full_name: Ciano Albanese, Naomi last_name: Ciano Albanese - first_name: Irmgard full_name: Amrein, Irmgard last_name: Amrein - first_name: Nathalie full_name: Vernoux, Nathalie last_name: Vernoux - first_name: Kaushik full_name: Sharma, Kaushik last_name: Sharma - first_name: Chin Wai full_name: Hui, Chin Wai last_name: Hui - first_name: Julie full_name: C. Savage, Julie last_name: C. Savage - first_name: Cristina full_name: Limatola, Cristina last_name: Limatola - first_name: Davide full_name: Ragozzino, Davide last_name: Ragozzino - first_name: Laura full_name: Maggi, Laura last_name: Maggi - first_name: Igor full_name: Branchi, Igor last_name: Branchi - first_name: Marie Ève full_name: Tremblay, Marie Ève last_name: Tremblay 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 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 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. 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. 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. 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. date_created: 2021-08-22T22:01:21Z date_published: 2021-10-01T00:00:00Z date_updated: 2023-10-03T09:49:18Z day: '01' department: - _id: GaNo doi: 10.1016/j.bbi.2021.07.022 external_id: isi: - '000702878400007' pmid: - '34343616' intvolume: ' 97' isi: 1 language: - iso: eng main_file_link: - open_access: '1' url: https://www.zora.uzh.ch/id/eprint/208855/1/ZORA208855.pdf month: '10' oa: 1 oa_version: Submitted Version page: 423-439 pmid: 1 publication: Brain, Behavior, and Immunity publication_identifier: issn: - 0889-1591 publication_status: published publisher: Elsevier quality_controlled: '1' scopus_import: '1' status: public title: Microglial-glucocorticoid receptor depletion alters the response of hippocampal microglia and neurons in a chronic unpredictable mild stress paradigm in female mice type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 97 year: '2021' ... --- _id: '8730' abstract: - lang: eng text: P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict at the blood–brain barrier (BBB) the brain distribution of the majority of currently known molecularly targeted anticancer drugs. To improve brain delivery of dual ABCB1/ABCG2 substrates, both ABCB1 and ABCG2 need to be inhibited simultaneously at the BBB. We examined the feasibility of simultaneous ABCB1/ABCG2 inhibition with i.v. co-infusion of erlotinib and tariquidar by studying brain distribution of the model ABCB1/ABCG2 substrate [11C]erlotinib in mice and rhesus macaques with PET. Tolerability of the erlotinib/tariquidar combination was assessed in human embryonic stem cell-derived cerebral organoids. In mice and macaques, baseline brain distribution of [11C]erlotinib was low (brain distribution volume, VT,brain < 0.3 mL/cm3). Co-infusion of erlotinib and tariquidar increased VT,brain in mice by 3.0-fold and in macaques by 3.4- to 5.0-fold, while infusion of erlotinib alone or tariquidar alone led to less pronounced VT,brain increases in both species. Treatment of cerebral organoids with erlotinib/tariquidar led to an induction of Caspase-3-dependent apoptosis. Co-infusion of erlotinib/tariquidar may potentially allow for complete ABCB1/ABCG2 inhibition at the BBB, while simultaneously achieving brain-targeted EGFR inhibition. Our protocol may be applicable to enhance brain delivery of molecularly targeted anticancer drugs for a more effective treatment of brain tumors. article_processing_charge: No article_type: original author: - first_name: N full_name: Tournier, N last_name: Tournier - first_name: S full_name: Goutal, S last_name: Goutal - first_name: S full_name: Mairinger, S last_name: Mairinger - first_name: IH full_name: Lozano, IH last_name: Lozano - first_name: T full_name: Filip, T last_name: Filip - first_name: M full_name: Sauberer, M last_name: Sauberer - first_name: F full_name: Caillé, F last_name: Caillé - first_name: L full_name: Breuil, L last_name: Breuil - first_name: J full_name: Stanek, J last_name: Stanek - first_name: AF full_name: Freeman, AF last_name: Freeman - first_name: Gaia full_name: Novarino, Gaia id: 3E57A680-F248-11E8-B48F-1D18A9856A87 last_name: Novarino orcid: 0000-0002-7673-7178 - first_name: C full_name: Truillet, C last_name: Truillet - first_name: T full_name: Wanek, T last_name: Wanek - first_name: O full_name: Langer, O last_name: Langer citation: ama: Tournier N, Goutal S, Mairinger S, et al. Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib. Journal of Cerebral Blood Flow and Metabolism. 2021;41(7):1634-1646. doi:10.1177/0271678X20965500 apa: Tournier, N., Goutal, S., Mairinger, S., Lozano, I., Filip, T., Sauberer, M., … Langer, O. (2021). Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib. Journal of Cerebral Blood Flow and Metabolism. SAGE Publications. https://doi.org/10.1177/0271678X20965500 chicago: Tournier, N, S Goutal, S Mairinger, IH Lozano, T Filip, M Sauberer, F Caillé, et al. “Complete Inhibition of ABCB1 and ABCG2 at the Blood-Brain Barrier by Co-Infusion of Erlotinib and Tariquidar to Improve Brain Delivery of the Model ABCB1/ABCG2 Substrate [11C]Erlotinib.” Journal of Cerebral Blood Flow and Metabolism. SAGE Publications, 2021. https://doi.org/10.1177/0271678X20965500. ieee: N. Tournier et al., “Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib,” Journal of Cerebral Blood Flow and Metabolism, vol. 41, no. 7. SAGE Publications, pp. 1634–1646, 2021. ista: Tournier N, Goutal S, Mairinger S, Lozano I, Filip T, Sauberer M, Caillé F, Breuil L, Stanek J, Freeman A, Novarino G, Truillet C, Wanek T, Langer O. 2021. Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib. Journal of Cerebral Blood Flow and Metabolism. 41(7), 1634–1646. mla: Tournier, N., et al. “Complete Inhibition of ABCB1 and ABCG2 at the Blood-Brain Barrier by Co-Infusion of Erlotinib and Tariquidar to Improve Brain Delivery of the Model ABCB1/ABCG2 Substrate [11C]Erlotinib.” Journal of Cerebral Blood Flow and Metabolism, vol. 41, no. 7, SAGE Publications, 2021, pp. 1634–46, doi:10.1177/0271678X20965500. short: N. Tournier, S. Goutal, S. Mairinger, I. Lozano, T. Filip, M. Sauberer, F. Caillé, L. Breuil, J. Stanek, A. Freeman, G. Novarino, C. Truillet, T. Wanek, O. Langer, Journal of Cerebral Blood Flow and Metabolism 41 (2021) 1634–1646. date_created: 2020-11-06T08:39:01Z date_published: 2021-07-01T00:00:00Z date_updated: 2023-10-18T06:45:30Z day: '01' department: - _id: GaNo doi: 10.1177/0271678X20965500 external_id: isi: - '000664214100012' pmid: - '33081568' intvolume: ' 41' isi: 1 issue: '7' language: - iso: eng main_file_link: - open_access: '1' url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221757/ month: '07' oa: 1 oa_version: Published Version page: 1634-1646 pmid: 1 publication: Journal of Cerebral Blood Flow and Metabolism publication_identifier: eissn: - 1559-7016 issn: - 0271-678x publication_status: published publisher: SAGE Publications quality_controlled: '1' scopus_import: '1' status: public title: Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 41 year: '2021' ...