Oligodendrocyte phenotyping and drug screening in schizophrenia cellular and mouse models

Chang, Man-Hsin (2026): Oligodendrocyte phenotyping and drug screening in schizophrenia cellular and mouse models. Dissertation, LMU München: Faculty of Medicine

Abstract

Schizophrenia (SCZ) is a debilitating psychiatric disorder characterized by positive, negative, and cognitive symptoms. Current medications have limited efficacy, especially in negative and cognitive symptoms. A comprehensive understanding of the pathogenesis of SCZ is required for developing novel treatments with better efficacy. Oligodendrocytes (OLs) are a type of glial cell in the central nervous system, forming myelination, which is important for cognitive function. Several postmortem, genetic, and imaging studies have revealed the deficits of OLs and myelination in SCZ patients, suggesting their critical role in the pathogenesis of SCZ. To study OLs in SCZ-relevant phenotypes, cellular and mouse models were used in this study. Human induced pluripotent stem cell (hiPSC)-derived OLs (iOLs) were differentiated from the samples of SCZ patients and healthy controls. SCZ iOLs showed abnormally more complex morphology with increased branch length and junction numbers compared to control iOLs, indicating a premature phenotype. To screen myelination-stimulating compounds that can reverse the phenotypes in SCZ iOLs and further in mouse models, five compounds, including clemastine, montelukast, ketoconazole, miconazole, and PD0325901, each with two concentrations and two treatment durations, were first tested in iOLs from healthy controls. After treatment for three days, PD0325901 with 1 μM significantly increased the branch length and the junction number of iOLs. Several mouse models relevant to SCZ were used to study the role of OLs/myelination in SCZ. First, the poly(I:C) mouse model was studied due to the association of inflammation with SCZ. Moreover, the early life stress (ELS) paradigm was integrated as an environmental stressor. The brains of the offspring from poly(I:C)-treated pregnant mice with or without ELS and the controls were stained for MBP, NeuN, GFAP, and Iba1, which are the markers for myelination, neurons, astrocytes, and microglia, respectively. At postnatal day 7 (P7), GFAP levels were decreased in the prefrontal cortex (PFC), and Iba1 levels were increased in the PFC but decreased in the hippocampus in response to inflammation and stress. At P21, MBP levels were increased in the PFC, and NeuN levels were increased in the PFC and the hippocampus in response to poly(I:C)-induced inflammation and stress. However, the behavioral tests of poly(I:C)-exposed offspring showed no SCZ-relevant phenotypes. Thus, another model, Olig2-Tcf4 double heterozygous knock out (Olig2-Tcf4 KO) mice, was investigated. Olig2-Tcf4 KO mice showed increased locomotion, lower anxiety-like behavior, declined performance in place learning, abnormal prepulse inhibition, and impaired remote fear memory recall. To further recapitulate the real-life adversity, the ELS paradigm was integrated with Olig2-Tcf4 KO mice. While no significant SCZ-like phenotypes were demonstrated. In summary, OL impairments are clearly linked to SCZ with supportive cellular and animal findings. iOLs from SCZ patients showed abnormal morphology with increased branch length and junction numbers. In the mouse study, Olig2-Tcf4 KO mice exhibited impaired cognitive function in learning and remote fear memory recall. Thus, these findings in this study provide a foundation to further study the thorough mechanisms and compound screening for developing novel treatments.

• Item Type: Theses (Dissertation, LMU Munich)
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 10. March 2026
• 1. Referee: Roßner, Moritz
• Signature of the printed copy: 0700/UMD 22739