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Scientists showed that the genetic risk for schizophrenia accumulates not only in neurons, but also in oligodendrocytes. For the first time, they are now able to name a mechanism behind the cognitive disorders seen in schizophrenia. Several previous findings have linked impairments of oligodendrocytes and myelination with schizophrenia. The researches now wanted to know more about the morphology and properties of schizophrenia oligodendrocytes, specifically whether impairments are a secondary consequence of neuronal deficits or, at least in parts, genetically driven and cell-autonomous.
Schizophrenia is a debilitating mental disorder affecting around 1 per cent of the population worldwide, and is notoriously difficult to treat. Current medications for schizophrenia can ameliorate positive symptoms, such as hallucinations and delusions. However, there is still a huge unmet medical need for treating negative symptoms, including social withdrawal and lack of motivation, and cognitive symptoms, including impaired attention and memory function.
Peter Falkai, Director of the LMU University Hospital of Psychiatry and Director of the Research Hospital of the Max Planck Institute of Psychiatry (MPI), and his team led by former PhD student from the International Max Planck Research School for Translational Psychiatry (IMPRS-TP) Florian Raabe, established a rapid and robust protocol for induced-pluripotent stem cell (iPSC)-derived oligodendrocytes. Oligodendrocytes are a type of cell in the nervous system that produce myelin, which insulates a neuron’s axon, thereby allowing signals to travel from neuron to neuron more quickly. Th team collected blood samples from schizophrenia patients with clinical white matter impairments to produce iPSCs, which differentiated into oligodendrocytes in the cell culture. Schizophrenia patients seem to show widespread white matter disturbances.
The scientists were curious about the morphology and properties of the schizophrenia oligodendrocytes. Surprisingly, the LMU team, alongside IMPRS student and first author of the recently published study Man-Hsin Chang, revealed a more complex morphology in these schizophrenia oligodendrocytes compared to iPSC-derived oligodendrocytes from healthy controls. These schizophrenia oligodendrocytes seemed to be more “mature” than the control oligodendrocytes in the cell culture, which is quite interesting as most postmortem studies show impaired oligodendrocytes and disturbed myelination in the brain of schizophrenia patients.
The team hypothesized that this feature could indicate a “prematuration” phenotype in the early developmental stage of oligodendrocytes. The protocol used in this study allowed the team to look only at the early stages of development, which is quite different from the late stage of oligodendrocyte development seen in postmortem studies.
“This current study is just a preliminary investigation, there are still many experiments to work on. First, we would need to increase the sample size to see if these findings are applicable to a bigger cohort. Second, we would like to know the functionality of these schizophrenia oligodendrocytes: Whether their myelination capability is impeded as well and how they interact with other cells”, Raabe explains. He is now Leading Senior Physician at the MPI Research Hospital and will continue his work in culturing these oligodendrocytes with iPSC-derived neurons or even generate three-dimensional spheroids or organoids to recreate the environment of human brains.
Looking back, Falkai now summarizes many years of successful research: “In the initial postmortem study 13 years ago I thought the interneurons must be involved, but never dreamed that there would be also a reduction of the oligodendrocytes. Although we still can not confidently answer the question whether oligodendrocyte pathology is mainly primary or secondary in schizophrenia, we believe that oligodendrocytes definitely play a pivotal role in the pathogenesis of schizophrenia and serve as a novel target to develop better treatments. The very first mechanism for cognitive disorders in schizophrenia that we found should hopefully be further investigated in the coming years. Moreover, we believe that schizophrenia is a heterogeneous disorder. We only studied samples from schizophrenia patients with white matter deficits: If these phenotypes are specific to a certain group of patients, it may imply a potential stratification of patients for personalized medicine in the future.”
Translational Psychiatry, 2025
https://doi.org/10.1038/s41398-025-03509-x
https://www.psych.mpg.de/2959339/news_publication_25231450_transferred?c=1496360
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