Increasing SOX10 Expression Overcomes Schizophrenia-Associated Early Oligodendrocyte Growth Deficits In Vitro

Individuals with schizophrenia (SZ) tend to have lower than average brain myelin content. Gene-set analyses suggest that aberrant oligodendrocyte (OL) development is an underlying cause of this abnormality. Previously, we observed that cells from patients with SZ, reprogrammed to neural lines, had substantially reduced OL production. Furthermore, OLs produced in culture correlated strongly with myelin content observed in the brains of the donors of the lines. In the current study, we tested whether increasing expression of SOX10, crucial in determining commitment to oligodendrocyte fate, can overcome the SZ-associated deficit in OL production.

Fibroblasts from 6 participants with SZ and 6 healthy control participants were reprogrammed to neural lines. Quantitative reverse transcription polymerase chain reactions were run to determine the expression of SOX10. In addition, expression was measured for several other genes (OLIG2, SOX9, QK I, and FEZ1) that are associated with risk for SZ and also interact with SOX10 in determining OL development. Finally, using an inducible lentiviral system, SOX10 was expressed in neural precursor cells and the effect of increased SOX10 expression on the production of OLs was quantified.

SOX10 expression was significantly reduced in cells from patients with SZ. Reductions in expression of SOX9 and QK I were also seen. Increasing SOX10 gene and resulting protein expression overcame the SZ-associated deficit in OL production.

Evidence from these studies, together with previous results, suggests that reduced SOX10 is a critical determinant of deficient OL production and, thereby, a contributing determinant of abnormal brain myelination in SZ. This abnormality could be a target for therapeutic interventions.