Periodic Reporting for period 3 - SCHIZTYPE (Brain cell type-specific interactions and schizophrenia)
Période du rapport: 2022-04-01 au 2023-09-30
Schizophrenia is a debilitating disorder affecting millions of people worldwide with a huge cost to those affected, those that care for them, and to society. Schizophrenia is largely a genetic disorder in that the risk of getting schizophrenia is determined by the DNA code that we inherit from our parents. Thanks to recent advances in human genetic studies we now know more about the complex architecture of the genetic risk where a vast majority of schizophrenia cases are due to a combination of hundreds of risk mutations, each contributing a small amount of risk. How schizophrenia arises in the brain of patients is however not understood. Schizophrenia has been shown to be complex also in terms of cellular pathology in patients with most cell types having been implicated at some point. However, our previous analysis has indicated that all the risk genes, based on where these genes are used, point towards a limited set of brain cells being central to the risk of getting schizophrenia. Cortical excitatory (increases activity) cell classes have the highest signal while less signal was observed in oligodendrocytes (support cells) and inhibitory (decrease activity) neurons. Nonetheless, these two latter classes have repeatedly been shown to be affected in the brains of patients that suffered from the disorder. In SCHIZTYPE we first aim to identify the genetic programs inside cortical excitatory neurons that are changed in disease using mouse models and human postmortem brains. Once we know this we want to use this knowledge to manipulate these genetic programs specifically in excitatory neurons and see if that can cause the observed changes in oligodendrocytes and inhibitory neurons. Showing this connection will help to explain how disease-related changes in one cell can propagate through the cellular networks of the brain. Proving that this is the case will help schizophrenia research to sift through the complexity of both the brain and schizophrenia to better focus our efforts to find treatment strategies.
We have to date performed used a method called single-cell sequencing, which measures how much of each gene is being used in each cell type, in 5 different mouse models for schizophrenia risk. This has revealed gene networks that are changed in cortical excitatory neurons and we are now confirming which of these also can be observed in human post mortem brain tissue from schizophrenia patients. Our findings so far confirm our prediction that it is indeed the cortical excitatory neurons that are the most affected - both in mouse models and patients. We are now moving into the second phase of the project in which we are developing virus-based methods to perturb those genetic programs in otherwise normal mice to study how other cell types react to these changes.
We expect our findings to shed light on how schizophrenia-related pathological changes can spread within the brain's networks.