Neurodevelopmental Alterations in Idiopathic and Isogenic iPSC-derived Psychiatric Disease Models

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dc.contributor.advisor Volkmer, Hansjürgen (Prof. Dr.)
dc.contributor.author Heider, Johanna
dc.date.accessioned 2024-10-01T09:08:23Z
dc.date.available 2024-10-01T09:08:23Z
dc.date.issued 2024-10-01
dc.identifier.uri http://hdl.handle.net/10900/157739
dc.identifier.uri http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1577398 de_DE
dc.identifier.uri http://dx.doi.org/10.15496/publikation-99071
dc.description.abstract Deregulated synaptic connectivity and neuronal activity are suggested to play an important role in the pathology of neuropsychiatric disorders. According to a popular hypothesis in the field, an imbalance between excitatory and inhibitory neurotransmission in the prefrontal cortical microcircuitry contributes to a disruption of neuronal network activity, which is involved in higher cognitive processing and affected in neuropsychiatric diseases such as schizophrenia spectrum disorder (SCZ). SCZ is a spectrum of severe and highly complex neurodevelopmental diseases, characterized by a variety of symptoms including hallucinations, emotional and cognitive deficits. Genetic risk, as well as adverse environmental impacts to the developing brain (e.g. neuroinflammation) are thought to contribute to the manifestation of the disease. To date, there is no curative treatment for SCZ, which can partially be attributed to the lack of functional insight into the underlying cellular and molecular mechanisms. To investigate excitation-inhibition imbalance in SCZ and related neuropsychiatric diseases, an optimized human in vitro model of the developing cortical microcircuitry, composed of induced pluripotent stem cell (iPSC)-derived glutamatergic and GABAergic cortical neurons was employed (E-I co-cultures). Two approaches of in vitro disease modeling were explored: both iPSC derived directly from patients with idiopathic SCZ, as well as an isogenic disease model in which mutations in iPSC were introduced into the neuropsychiatric risk gene DISC1, were studied. Patient-derived neural progenitor cells revealed decreased neuronal differentiation efficiency and altered cell cycle control. For the first time, cell-type specific analysis was employed in patient-derived E-I co-cultures, which identified aberrant synapse formation and altered neuronal single-cell and network activity in SCZ. To investigate the impact of neuroinflammation on synapse formation, patient-derived microglia were added to E-I co-cultures. Here, a reduction of inhibitory synaptic terminals was observed, suggesting a cell-type specific aberrant microglia-neuron interaction. To generate an isogenic disease model, mutations were introduced into the neuropsychiatric risk gene DISC1 in a healthy iPSC line using CRISPR-Cas9 gene-editing. In mutant E-I co-cultures, synaptic excitation-inhibition imbalance was shifted due to increased inhibitory input, which was linked to increased differentiation efficiency of mutant neurons towards the GABAergic lineage. Overall, the E-I co-culture system provided novel insights into synaptic connectivity and neuronal functionality in psychiatric diseases. Idiopathic and isogenic disease models shared synaptic excitation-inhibition imbalance as an overarching phenotype, although different types of neurons were primarily affected in the two models. en
dc.language.iso en de_DE
dc.publisher Universität Tübingen de_DE
dc.rights ubt-podno de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_ohne_pod.php?la=de de_DE
dc.rights.uri http://tobias-lib.uni-tuebingen.de/doku/lic_ohne_pod.php?la=en en
dc.subject.ddc 570 de_DE
dc.subject.other schizophrenia en
dc.subject.other induced pluripotent stem cells en
dc.subject.other disease model en
dc.subject.other neurodevelopment en
dc.subject.other microglia en
dc.subject.other co-culture en
dc.subject.other DISC1 en
dc.title Neurodevelopmental Alterations in Idiopathic and Isogenic iPSC-derived Psychiatric Disease Models en
dc.type PhDThesis de_DE
dcterms.dateAccepted 2024-09-23
utue.publikation.fachbereich Biologie de_DE
utue.publikation.fakultaet 7 Mathematisch-Naturwissenschaftliche Fakultät de_DE
utue.publikation.noppn yes de_DE

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