First mechanism of cognitive impairment in schizophrenia discovered

The classic story of schizophrenia is “neurons and synapses.” But growing evidence suggests that white matter is also affected, meaning oligodendrocytes, the cells that myelinate axons and support neurons metabolically. Researchers from Munich and colleagues took the problem “from both ends”: on the one hand, they grew oligodendrocytes and their precursors from human induced pluripotent cells (hiPSCs) and looked at how the genetic risk for schizophrenia falls on them. On the other, they formed a “translational” clinical cohort and selected patients based on MRI signs of white matter disorders. The result, in simple terms: the genetics of schizophrenia is associated with disorders of the oligodendrocyte program, and in patients with “bad” white matter, their iPSC oligodendrocytes already in culture look and behave differently - more branched and with an altered signaling/proliferative program.

Background of the study

For a long time, schizophrenia was considered primarily a "neuronal-synaptic" disorder. However, large MRI projects have shown that patients have widespread white matter impairment - the diffusion MRI pattern (decreased FA, increased RD) is best explained by myelination disorders. This is also important in terms of timing: active formation of white matter occurs from early childhood to adolescence and ends in young adulthood - just when most people experience their onset of symptoms. This means that not only neurons but also oligodendrocytes (OL), "myelinator" cells, which determine the speed of conduction and the consistency of networks, can participate in the pathogenesis.

This line is supported by postmortem studies and additional "omics": in schizophrenia, a decrease in the number of OLs, shifts in the expression of "myelin" genes, morphological changes, and even an imbalance of myelin lipids are described; and myelin deficiency is associated with cognitive impairment and slower information processing. In other words, part of the syndrome may come from the "white end" - through a defect in oligodendrocyte support and myelination of the conduction pathways.

Genetically, schizophrenia is a polygenic disorder with high heritability. Early GWAS analyses did find the greatest enrichment in neuronal sets, but more and more data point to a contribution of the oligodendrolineage. The key question arises: is it secondary to neurons or partially cell-autonomous? It is difficult to test this in living human tissue, so iPSC models with targeted differentiation into precursors and mature OL are used (including accelerated protocols with overexpression of SOX10/OLIG2/NKX6.2, the so-called SON approach). Such systems allow us to directly see how the genetic risk “falls” on the OL program.

A new paper in Translational Psychiatry bridges these gaps: the authors show that iPSC-OL/OPC transcriptional signatures are enriched in schizophrenia GWAS associations, and in patients preselected for prominent white matter abnormalities on DTI, their own iPSC-OL in culture exhibit hyperbranched morphology and disrupted signaling/proliferation pathways. This design both supports the cell-autonomous contribution of OL and suggests a practical approach: stratify patient subtypes by DTI/white matter and test “myelinocentric” interventions precisely where the oligodendrocyte axis is most vulnerable.

How was this tested?

The authors compared the transcriptomes of their hiPSC-oligodendrocytes/OPCs with single-cell data from postmortem human tissue and generated gene sets by differentiation stages; then, they performed competitive enrichment using the pooled GWAS statistics of schizophrenia (MAGMA tool). In parallel, diffusion tensor MRI was performed in a clinical cohort (N = 112) of people with schizophrenia and healthy controls, and participants were stratified by the degree of white matter impairment using DTI parameters; skin/blood cells were taken from the subgroup with severe impairment, reprogrammed into hiPSCs and differentiated into oligodendrocytes (patients N = 8, controls N = 7). Morphology (branching, branch length, number of nodes) and transcriptome were assessed in these “personalized” cells.

Main findings

• Oligodendrocytic signatures are enriched in schizophrenia genetics. hiPSC-OPC/OL profiles correlated well with human postmortem data, and their gene sets showed significant enrichment in schizophrenia GWAS associations, indicating a cell-autonomous contribution of the oligodendrolineage.
• The morphology of "mature" OL in patients is altered. In iPSC-OL from the schizophrenia group, the authors saw an increased total length of branches and a greater number of "junctions" - that is, hyperbranching compared to controls.
• Signaling and proliferation are "off". Transcriptomic analysis showed dysregulation of oligodendrocyte signaling and division pathways, which is logically combined with morphological shifts.
• In vivo brain connectivity. The strategy of selection via DTI-white matter (wide conduction disturbances, most likely due to myelin) helped to catch precisely those patients in whom the "oligo" component is most pronounced - and this feature was "transferred" to the Petri dish.

Why is this important?

Schizophrenia is polygenic, and genetic risk has long seemed to be almost entirely “neuronal.” This work adds the missing link: part of the risk manifests itself directly in oligodendrocytes and is not limited to secondary consequences of neuronal dysfunction. The practical implications are twofold. First, myelinocentric approaches (modulation of OL maturation, remyelination) gain a stronger biological foothold, especially for information processing symptoms and cognitive deficits, which are closely associated with white matter. Second, stratification by DTI may help to identify a subtype of patients in whom the oligodendrocyte axis is key, and in whom targeted interventions can be tested.

What's new in the methods and why you can trust them

The team relied on an already validated protocol of “accelerated” oligodendrocyte differentiation of hiPSCs overexpressing SOX10/OLIG2/NKX6.2 (SON) and carefully matched the “cellular” data with human postmortem profiles, avoiding typical pitfalls (smearing of variability during over-integration, conservative corrections for multiple comparisons). Critically, the clinical part was not limited to diagnosis: the DTI approach allowed “grounding” cellular phenotypes to individual features of white matter. In total, this increases confidence in the conclusion about the cell-autonomous component.

How does this fit with previous data?

Large multicenter MRI studies have shown that white matter is widely disrupted in schizophrenia, and the configuration of DTI indices most closely resembles a myelination defect, the very function for which OLs are responsible. Postmortem studies have found a decrease in the number of oligodendrocytes, changes in the expression of “myelin” genes, and morphological shifts in OLs. The new paper neatly “stitches” these three levels—genetics, the brain in vivo, and the cell—into a single causal line.

What could this mean next?

• Subtype biomarkers: Combinations of DTI metrics with circulating/cellular markers of oligodendrocyte pathways may form the basis for stratification and prognosis of cognitive outcomes.
• New points of intervention. The maturation pathway of OL, regulation of their branching and proliferation - candidates for pharmacological modulation and "accompaniment" to cognitive rehabilitation.
• iPSC platforms for screening. Personalized OL from patients with striking DTI disorders - a convenient testbed for testing compounds affecting myelin/branching/signaling.

Restrictions

This is an association study: it strongly suggests that the genetics of schizophrenia are linked to functional oligodendrocyte features, but it does not show that correcting a specific gene will “cure” the phenotype. The “cell” subset is small (8 patients/7 controls), and the DTI selection, while clever, makes the findings representative of a subtype with significant white matter abnormalities. Finally, branching morphology is not a direct measure of myelin; confirmation at the levels of electrical conductivity and remyelination is needed.

Briefly - three theses

• Genetic risk for schizophrenia is enriched in oligodendrocyte/OPC gene programs; the contribution of this lineage is cell-autonomous.
• In patients with white matter abnormalities, their iPSC-oligodendrocytes in culture have hyperbranched morphology and disrupted signaling/proliferation pathways.
• The DTI → iPSC-OL strategy provides a working basis for personalized tests and targeted interventions targeting myelination and cognitive function.

Source: Chang M.-H. et al. iPSC-modelling reveals genetic associations and morphological alterations of oligodendrocytes in schizophrenia. Translational Psychiatry, August 16, 2025. DOI: https://doi.org/10.1038/s41398-025-03509-x