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

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URI: http://hdl.handle.net/10900/157739
http://nbn-resolving.de/urn:nbn:de:bsz:21-dspace-1577398
http://dx.doi.org/10.15496/publikation-99071
Dokumentart: PhDThesis
Date: 2024-10-01
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Volkmer, Hansjürgen (Prof. Dr.)
Day of Oral Examination: 2024-09-23
DDC Classifikation: 570 - Life sciences; biology
Other Keywords:
schizophrenia
induced pluripotent stem cells
disease model
neurodevelopment
microglia
co-culture
DISC1
License: http://tobias-lib.uni-tuebingen.de/doku/lic_ohne_pod.php?la=de http://tobias-lib.uni-tuebingen.de/doku/lic_ohne_pod.php?la=en
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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.

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