SCHIZTYPE · Brain cell type-specific interactions and schizophrenia

Schizophrenia is a heritable but genetically complex disease. Pathological and epidemiological data fit a model of SCZ as a network disease with perturbations during brain development leading to early-adulthood onset clinical symptomatology. Our present understanding is based on single markers or arrays of gene expression from tissue samples containing multiple cell types. As a consequence, pathological changes in the function of inhibitory or excitatory neurons, microglia, or oligodendrocytes have variously been proposed to be the cause of symptoms. In light of recent data I hypothesize that it is unlikely that the various cellular SCZ-pathologies all arise independently from genetic alterations in multiple cell types. Recent findings from my lab show that in the cortex the expression of risk genes for SCZ are enriched in excitatory neurons, and that this set of risk-genes is largely non-overlapping with those expressed in other cell types. I propose that pathological genetic changes in excitatory cells ultimately initiates pathological changes in other cell types contributing to the multiple cellular pathologies observed in SCZ. We will:1. Identify cell type-specific gene regulatory networks involved in SCZ (SCZ-GRNs) in prefrontal cortical excitatory cells by analysis of four distinct SCZ mouse models.2. Confirm putative SCZ-GRNs in patient material using in situ transcriptomics on postmortem brains and connect to clinical features via collaboration with genomic studies in Sweden and Denmark.3. Functionally investigate the effects of perturbing excitatory cell SCZ-GRNs on other cell types.Single-cell RNA-seq, providing insights into the molecular properties of individual cells, and modern molecular tools for perturbing transcription in a cell type-specific way opens up for new knowledge of mechanisms underlying SCZ pathology. My work will identify causal relationships that can be exploited for the development of strategies for personalized treatment.