Myelination of axons in the nervous system of vertebrates, is crucial for effective impulse propagation. During brain development, oligodendrocyte lineage cells progress from mobile, electrically active oligodendrocyte precursor cells (OPCs) to myelinating oligodendrocytes. Human myelination takes years, peaking during the first years of life and continuing into late adulthood. Recent brain imaging and postmortem studies found that schizophrenia patients often display major myelination abnormalities.  This correlation could be driven by OPC differentiation-related myelination deficits, leading to brain-wide circuit dysfunction. However, the impact of schizophrenia risk genes on human OPC differentiation and myelination is unknown. One of the most penetrating genetic mutations in schizophrenia is in the Disrupted in Schizophrenia 1 (DISC1) gene. Studies in mouse primary cortical cell cultures suggest that OPCs are extremely sensitive to DISC1 levels. Remarkably, I show here that DISC1 is predominantly expressed in the human OPCs lineage during cortical development. Using a novel human pluripotent stem cell- derived three-dimensional oligodendrocyte organoid model, which was developed by my principal investigator, I will determine DISC1’s role in human oligodendrocyte lineage formation and neuro- glial interactions. My study will gain insight, for the first time, into a potential  causal  link between  genetically  associated  schizophrenia  and  myelination  deficits  in developing human brain tissue. The findings could eventually lead to innovations in drug development for this devastating disorder.

Supervisor: Dr. Omer Revah