--- _id: '13107' abstract: - lang: eng text: "Within the human body, the brain exhibits the highest rate of energy consumption amongst all organs, with the majority of generated ATP being utilized to sustain neuronal activity. Therefore, the metabolism of the mature cerebral cortex is geared towards preserving metabolic homeostasis whilst generating significant amounts of energy. This requires a precise interplay between diverse metabolic pathways, spanning from a tissue-wide scale to the level of individual neurons. Disturbances to this delicate metabolic equilibrium, such as those resulting from maternal malnutrition\r\nor mutations affecting metabolic enzymes, often result in neuropathological variants of neurodevelopment. For instance, mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), have been associated with autism and microcephaly. However, despite recent progress in the field, the extent of metabolic restructuring that occurs within the developing brain and the corresponding alterations in nutrient demands during various critical periods remain largely unknown. To investigate this, we performed metabolomic profiling of the murine cerebral cortex to characterize the metabolic state of the forebrain at different developmental stages. We found that the developing cortex undergoes substantial metabolic reprogramming, with specific sets of metabolites displaying stage-specific changes. According to our observations, we determined a distinct temporal period in postnatal development during which the cortex displays heightened reliance on LNAAs. Hence, using a conditional knock-out mouse model, we deleted Slc7a5 in neural cells, allowing us to monitor the impact of a perturbed neuronal metabolic state across multiple developmental stages of corticogenesis. We found that manipulating the levels of essential LNAAs in cortical neurons in vivo affects one particular perinatal developmental period critical for cortical network refinement. Abnormally low intracellular LNAA levels result in cell-autonomous alterations in neuronal lipid metabolism, excitability, and survival during this particular time window. Although most of the effects of Slc7a5 deletion on neuronal physiology are transient, derailment of these processes during this brief but crucial window leads to long-term circuit dysfunction in mice. In conclusion, out data indicate that the cerebral cortex undergoes significant metabolic reorganization during development. This process involves the intricate integration of multiple metabolic pathways to ensure optimal neuronal function throughout different developmental stages. Our findings offer a paradigm for understanding how neurons synchronize the expression of nutrient-related genes with their activity to allow proper brain maturation. Further, our results demonstrate that disruptions in these precisely calibrated metabolic processes during critical periods of brain development may result in neuropathological outcomes in mice and in humans." acknowledged_ssus: - _id: PreCl - _id: Bio - _id: EM-Fac alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Lisa full_name: Knaus, Lisa id: 3B2ABCF4-F248-11E8-B48F-1D18A9856A87 last_name: Knaus citation: ama: 'Knaus L. The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival. 2023. doi:10.15479/at:ista:13107' apa: 'Knaus, L. (2023). The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival. Institute of Science and Technology Austria. https://doi.org/10.15479/at:ista:13107' chicago: 'Knaus, Lisa. “The Metabolism of the Developing Brain : How Large Neutral Amino Acids Modulate Perinatal Neuronal Excitability and Survival.” Institute of Science and Technology Austria, 2023. https://doi.org/10.15479/at:ista:13107.' ieee: 'L. Knaus, “The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival,” Institute of Science and Technology Austria, 2023.' ista: 'Knaus L. 2023. The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival. Institute of Science and Technology Austria.' mla: 'Knaus, Lisa. The Metabolism of the Developing Brain : How Large Neutral Amino Acids Modulate Perinatal Neuronal Excitability and Survival. Institute of Science and Technology Austria, 2023, doi:10.15479/at:ista:13107.' short: 'L. Knaus, The Metabolism of the Developing Brain : How Large Neutral Amino Acids Modulate Perinatal Neuronal Excitability and Survival, Institute of Science and Technology Austria, 2023.' date_created: 2023-06-01T09:05:24Z date_published: 2023-05-31T00:00:00Z date_updated: 2024-02-07T08:03:33Z day: '31' ddc: - '570' degree_awarded: PhD department: - _id: GradSch - _id: GaNo doi: 10.15479/at:ista:13107 ec_funded: 1 file: - access_level: closed checksum: 4b69a4ac0bbf4163d59c0b58dcb4f2c3 content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document creator: lknaus date_created: 2023-06-01T13:48:41Z date_updated: 2023-06-01T13:48:41Z file_id: '13112' file_name: Thesis_Lisa Knaus_approved_final.docx file_size: 12991551 relation: source_file - access_level: open_access checksum: 6903d152aa01181d87a696085af31c83 content_type: application/pdf creator: lknaus date_created: 2023-06-02T09:47:29Z date_updated: 2023-06-07T08:41:49Z file_id: '13114' file_name: Thesis_Lisa Knaus_approved_final_pdfa2b.pdf file_size: 9309015 relation: main_file file_date_updated: 2023-06-07T08:41:49Z has_accepted_license: '1' language: - iso: eng month: '05' oa: 1 oa_version: Published Version page: '147' 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_identifier: issn: - 2663 - 337X publication_status: published publisher: Institute of Science and Technology Austria related_material: record: - id: '12802' 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: 'The metabolism of the developing brain : How large neutral amino acids modulate perinatal neuronal excitability and survival' type: dissertation user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9 year: '2023' ... --- _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: '8620' abstract: - lang: eng text: "The development of the human brain occurs through a tightly regulated series of dynamic and adaptive processes during prenatal and postnatal life. A disruption of this strictly orchestrated series of events can lead to a number of neurodevelopmental conditions, including Autism Spectrum Disorders (ASDs). ASDs are a very common, etiologically and phenotypically heterogeneous group of disorders sharing the core symptoms of social interaction and communication deficits and restrictive and repetitive interests and behaviors. They are estimated to affect one in 59 individuals in the U.S. and, over the last three decades, mutations in more than a hundred genetic loci have been convincingly linked to ASD pathogenesis. Yet, for the vast majority of these ASD-risk genes their role during brain development and precise molecular function still remain elusive.\r\nDe novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin 3 (CUL3) lead to ASD. In the study described here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 heterozygous knockout mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3+/-, Cul3+/fl Emx1-Cre and Cul3fl/fl Emx1-Cre mutant brains display cortical lamination abnormalities due to defective migration of post-mitotic excitatory neurons, as well as reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal cortical organization, Cul3 heterozygous deletion is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level we show that Cul3 regulates cytoskeletal and adhesion protein abundance in the mouse embryonic cortex. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neural cells results in atypical organization of the actin mesh at the cell leading edge. Of note, heterozygous deletion of Cul3 in adult mice does not induce the majority of the behavioral defects observed in constitutive Cul3 haploinsufficient animals, pointing to a critical time-window for Cul3 deficiency.\r\nIn conclusion, our data indicate that Cul3 plays a critical role in the regulation of cytoskeletal proteins and neuronal migration. ASD-associated defects and behavioral abnormalities are primarily due to dosage sensitive Cul3 functions at early brain developmental stages." acknowledged_ssus: - _id: Bio - _id: PreCl acknowledgement: I would like to especially thank Armel Nicolas from the Proteomics and Christoph Sommer from the Bioimaging Facilities for the data analysis, and to thank the team of the Preclinical Facility, especially Sabina Deixler, Angela Schlerka, Anita Lepold, Mihalea Mihai and Michael Schun for taking care of the mouse line maintenance and their great support. alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Jasmin full_name: Morandell, Jasmin id: 4739D480-F248-11E8-B48F-1D18A9856A87 last_name: Morandell citation: ama: Morandell J. Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. 2020. doi:10.15479/AT:ISTA:8620 apa: Morandell, J. (2020). Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:8620 chicago: Morandell, Jasmin. “Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis.” Institute of Science and Technology Austria, 2020. https://doi.org/10.15479/AT:ISTA:8620. ieee: J. Morandell, “Illuminating the role of Cul3 in autism spectrum disorder pathogenesis,” Institute of Science and Technology Austria, 2020. ista: Morandell J. 2020. Illuminating the role of Cul3 in autism spectrum disorder pathogenesis. Institute of Science and Technology Austria. mla: Morandell, Jasmin. Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis. Institute of Science and Technology Austria, 2020, doi:10.15479/AT:ISTA:8620. short: J. Morandell, Illuminating the Role of Cul3 in Autism Spectrum Disorder Pathogenesis, Institute of Science and Technology Austria, 2020. date_created: 2020-10-07T14:53:13Z date_published: 2020-10-12T00:00:00Z date_updated: 2023-09-07T13:22:14Z day: '12' ddc: - '610' degree_awarded: PhD department: - _id: GaNo doi: 10.15479/AT:ISTA:8620 file: - access_level: open_access checksum: 7ee83e42de3e5ce2fedb44dff472f75f content_type: application/pdf creator: jmorande date_created: 2020-10-07T14:41:49Z date_updated: 2021-10-16T22:30:04Z embargo: 2021-10-15 file_id: '8621' file_name: Jasmin_Morandell_Thesis-2020_final.pdf file_size: 16155786 relation: main_file - access_level: closed checksum: 5e0464af453734210ce7aab7b4a92e3a content_type: application/x-zip-compressed creator: jmorande date_created: 2020-10-07T14:45:07Z date_updated: 2021-10-16T22:30:04Z embargo_to: open_access file_id: '8622' file_name: Jasmin_Morandell_Thesis-2020_final.zip file_size: 24344152 relation: source_file file_date_updated: 2021-10-16T22:30:04Z has_accepted_license: '1' language: - iso: eng month: '10' oa: 1 oa_version: Published Version page: '138' project: - _id: 2548AE96-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: W1232-B24 name: Molecular Drug Targets - _id: 05A0D778-7A3F-11EA-A408-12923DDC885E grant_number: F07807 name: Neural stem cells in autism and epilepsy publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria related_material: record: - id: '7800' relation: part_of_dissertation status: public - id: '8131' 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: Illuminating the role of Cul3 in autism spectrum disorder pathogenesis type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2020' ... --- _id: '395' abstract: - lang: eng text: 'Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. Despite the remarkable number of scientific breakthroughs of the last 100 years, the treatment of neurodevelopmental disorders (e.g. autism spectrum disorder, intellectual disability, epilepsy) remains a great challenge. Recent advancements in geno mics, like whole-exome or whole-genome sequencing, have enabled scientists to identify numerous mutations underlying neurodevelopmental disorders. Given the few hundred risk genes that were discovered, the etiological variability and the heterogeneous phenotypic outcomes, the need for genotype -along with phenotype- based diagnosis of individual patients becomes a requisite. Driven by this rationale, in a previous study our group described mutations, identified via whole - exome sequencing, in the gene BCKDK – encoding for a key regulator of branched chain amin o acid (BCAA) catabolism - as a cause of ASD. Following up on the role of BCAAs, in the study described here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized mainly at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation and severe neurolo gical abnormalities. Additionally, deletion of Slc7a5 from the neural progenitor cell population leads to microcephaly. Interestingly, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Furthermore, whole - exome sequencing of patients diagnosed with neurological dis o r ders helped us identify several patients with autistic traits, microcephaly and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. In conclusion, our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for t he BCAA s in human bra in function. Together with r ecent studies (described in chapter two) that have successfully made the transition into clinical practice, our findings on the role of B CAAs might have a crucial impact on the development of novel individualized therapeutic strategies for ASD. ' acknowledged_ssus: - _id: PreCl - _id: EM-Fac - _id: Bio alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Dora-Clara full_name: Tarlungeanu, Dora-Clara id: 2ABCE612-F248-11E8-B48F-1D18A9856A87 last_name: Tarlungeanu citation: ama: Tarlungeanu D-C. The branched chain amino acids in autism spectrum disorders . 2018. doi:10.15479/AT:ISTA:th_992 apa: Tarlungeanu, D.-C. (2018). The branched chain amino acids in autism spectrum disorders . Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:th_992 chicago: Tarlungeanu, Dora-Clara. “The Branched Chain Amino Acids in Autism Spectrum Disorders .” Institute of Science and Technology Austria, 2018. https://doi.org/10.15479/AT:ISTA:th_992. ieee: D.-C. Tarlungeanu, “The branched chain amino acids in autism spectrum disorders ,” Institute of Science and Technology Austria, 2018. ista: Tarlungeanu D-C. 2018. The branched chain amino acids in autism spectrum disorders . Institute of Science and Technology Austria. mla: Tarlungeanu, Dora-Clara. The Branched Chain Amino Acids in Autism Spectrum Disorders . Institute of Science and Technology Austria, 2018, doi:10.15479/AT:ISTA:th_992. short: D.-C. Tarlungeanu, The Branched Chain Amino Acids in Autism Spectrum Disorders , Institute of Science and Technology Austria, 2018. date_created: 2018-12-11T11:46:14Z date_published: 2018-03-01T00:00:00Z date_updated: 2023-09-07T12:38:59Z day: '01' ddc: - '570' - '616' degree_awarded: PhD department: - _id: GaNo doi: 10.15479/AT:ISTA:th_992 file: - access_level: closed checksum: 9f5231c96e0ad945040841a8630232da content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document creator: dernst date_created: 2019-04-05T09:19:17Z date_updated: 2021-02-11T23:30:15Z embargo_to: open_access file_id: '6217' file_name: 2018_Thesis_Tarlungeanu_source.docx file_size: 43684035 relation: source_file - access_level: open_access checksum: 0c33c370aa2010df5c552db57a6d01e9 content_type: application/pdf creator: dernst date_created: 2019-04-05T09:19:17Z date_updated: 2021-02-11T11:17:16Z embargo: 2018-03-15 file_id: '6218' file_name: 2018_Thesis_Tarlungeanu.pdf file_size: 30511532 relation: main_file file_date_updated: 2021-02-11T23:30:15Z has_accepted_license: '1' language: - iso: eng month: '03' oa: 1 oa_version: Published Version page: '88' project: - _id: 25473368-B435-11E9-9278-68D0E5697425 call_identifier: FWF grant_number: F03523 name: Transmembrane Transporters in Health and Disease publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria publist_id: '7434' pubrep_id: '992' related_material: record: - id: '1183' 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: 'The branched chain amino acids in autism spectrum disorders ' 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: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2018' ...