Grant: Team Grant: NEURON

Schizophrenia is a heritable neurodevelopmental disorder affecting 0.5% of the world population. Symptoms include hallucinations, delusions as well as impaired cognition, attention and social interactions. The underlying brain pathology is abnormal function of a particular type of neuron, the fast-spiking inhibitory interneuron. Recent findings also implicate the abnormal integrity of myelin, a fatty substance that coats nerve cell projections and is essential for efficient neuronal signal propagation. Myelin is produced solely by oligodendrocytes, a non-neuronal cell type in the brain. Schizophrenia patient studies suggest myelination impairments could be a critical determinant of the disease. Yet, the mechanisms linking oligodendrocyte lineage cell dysfunction to schizophrenia are unknown. Our team has discovered unique properties of interneuron myelination and critical forms of communication between interneurons and oligodendrocyte precursor cells (OPCs). Given their intrinsic regenerative capacity as the cell type responsible for generating oligodendrocytes in the adult brain, OPCs represent a potential therapeutic target for enhancing the repair of myelin deficiencies in schizophrenia. Notably, we recently discovered that OPCs derived from genetically-identified familial schizophrenia patients have impaired function and defective myelination potential. Thus, we propose that schizophrenia is likely to be, at least in part, an OPC disease ("OPCphrenia"), arising from aberrant interneuron-OPC communication. In this proposal, we will dissect interneuron-OPC communication and investigate potential therapeutic rescue strategies for aberrant schizophrenia-related OPC dysfunction by re-balancing the levels of interneuron-secreted factors. We will leverage novel methodological advances, mouse genetics, and human patient samples to advance the understanding of schizophrenia pathophysiology and identify new molecular targets for future therapeutic intervention.