Project description
Unveiling the molecular aetiology of schizophrenia
Accumulating evidence suggests that schizophrenia emerges from perturbations during brain development. Data indicate that symptoms are caused by different pathological changes in excitatory neurons, microglia and oligodendrocytes. The EU-funded SCHIZTYPE project is working under the hypothesis that excitatory cells acquire genetic changes in risk genes for schizophrenia and ultimately induce changes in other cell types. Researchers will investigate cell type-specific gene regulatory networks in excitatory neurons and study the functional impact on other cell types. The project's results have the potential to explain the multiple cellular pathologies observed in schizophrenia and unveil the molecular aetiology of the disease.
Objective
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.
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Funding Scheme
ERC-COG - Consolidator GrantHost institution
17177 Stockholm
Sweden