Studying and modulating schizophrenia-associated dysfunctions of oligodendrocytes with patient-specific cell systems

Primary and secondary cell types and mechanisms of schizophrenia (SCZ)—combining results of the latest genome-wide association studies (GWASs) with cell type-specific transcriptomics. Most recent GWASs combined with single-cell RNAseq profiles identified SCZ risk genes that may primarily operate in three neuronal cell types: GABAergic medium spiny neurons (cyan), glutamatergic pyramidal neurons (red) and GABAergic cortical interneurons (blue). A minor fraction of single nucleotide polymorphisms associated with increased risk for SCZ may affect oligodendrocyte precursor cells (OPCs) and oligodendrocytes and their function (yellow). Nonetheless, oligodendroglia intensively interact with pyramidal projection neurons and cortical interneurons at the level of myelination and metabolic support. Myelination of long-range projection neurons supports the connectivity between brain regions (‘macro-connectivity’). Myelination and trophic support of interneurons may support the function of local circuits (’micro-connectivity’). Therefore, we hypothesize that the disturbed functional connectivity in SCZ results from the interaction of cell types and mechanisms where the primary effects occur (e.g. directed at synapses in glutamatergic and GABAergic neurons), with secondary effects on OPCs and oligodendrocytes finally causing white matter alterations. It is tempting to speculate that (i) positive symptoms are likely more connected to the dysfunction of dopamine-responsive medium spiny neurons and (ii) excitation-inhibition dysbalances of cortical glutamatergic and GABAergic neurons and disturbed connectivity, including oligodendroglia functions, may rather be associated with higher order cognitive impairments and negative symptom