Schizophrenia is perhaps the most human-specific psychopathology. It is one of the most severe - and common - psychiatric disorders, a cause of tremendous disability, distress and expense, and yet little remains clear about its etiology. That said, the specificity of schizophrenia to humans, and its frequent association in lesser forms with creativity, suggest its association with specifically human neural competencies. Paradoxically though, gene association studies have highlighted the association of oligodendrocytic and white matter genes with schizophrenia, rather than the neuronal genes that one might have expected of a pathology so uniquely human. Similarly, recent radiographic studies have highlighted the early appearance of hypomyelination in schizophrenics, often long before disease onset. These observations suggest that the aberrant features of neuronal organization and neuritic structure noted in schizophrenics might derive from glial progenitor and/or oligodendrocytic pathology, with progenitor dysregulation, dysmyelination and failed oligodendrocytic support of neurons yielding a developmentally-disrupted network structure. In this application, we will focus on the roles of OPCs and oligodendroglia in the genesis of schizophrenia, using a novel set of technologies by which we can produce chimeric mice whose glial populations have been largely replaced by hiPSC-derived glia, themselves derived from patients with juvenile-onset schizophrenia. By using congenitally hypomyelinated shiverer mice as hosts, we can generate mice whose white matter glia and myelin are almost entirely of human origin, with complete replacement of host OPCs and oligodendroglia by human cells. To establish the feasibility of this proposal, we established human glial chimeras in myelin-deficient shiverer mice, using schizophrenia-derived hiPSC OPCs. We found that the resultant human glial chimeric mice - which typically myelinate well following neonatal human OPC transplants - instead phenocopied the hypomyelination so characteristic of schizophrenic patients, with aberrant OPC dispersal and migration accompanying overt capsular and callosal dysmyelination. On that basis, we now propose to study the anatomy and transcriptional architecture of the white matter of these mice, focusing on the distribution of their engrafted OPCs relative to normal control hiPSC OPCs, as well as on oligodendrocytic differentiation and myelin formation by schizophrenia-derived hiPSC OPCs. We will then investigate their gene expression patterns, in terms of both mRNA and miRNA, the latter so as to define any higher-order transcriptional dysregulation that may be experienced by the schizophrenia-derived hiPSC OPCs. By providing a new human glial chimeric model system, new cellular reagents in the form of schizophrenic patient-derived OPCs, and new phenotype-specific and disease-associated gene expression databases, this project will make available a broad and exciting new set of tools, capabilities and databases. Together, these studies should provide us great insight into the role of glial progenitor cells and their derived myelin in the pathogenesis of schizophrenia.
The use of human glial chimeric mouse brains, characterized by the virtually complete replacement of host glial progenitors, oligodendrocytes and myelin by their human counterparts, offers us new opportunities for studying both the normal functions of human glia in vivo, as well the species-specific contributions of human glia to disease pathogenesis. At the same time, our development of efficient protocols for the generation of human OPCs from patient-derived hiPSCs allows us to produce oligodendroglia from patients with juvenile- onset schizophrenia. By pairing these techniques, we propose to establish human glial chimeric mice whose brains are comprised primarily of OPCs derived from schizophrenic patients, and to use these mice as platforms from which to study the anatomic, behavioral and genomic effects of schizophrenic oligodendroglia and myelin, in real-time and in vivo, in adult animals.