The role of cholesterol metabolism during neurodevelopment in the context of schizophrenia

• Grant number: 22/03335-2
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: July 29, 2022
• End date: July 28, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Daniel Martins-de-Souza
• Grantee: Fernanda Crunfli
• Supervisor: Sâmia Regiane Lourenço Joca
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Aarhus University, Denmark
• Associated to the scholarship: 19/22398-2 - The role of cholesterol synthesis in the mode of action of clozapine in schizophrenia models, BP.PD

Abstract

The brain is the most cholesterol-rich organ, accounting for 25% of the total cholesterol present in the human body, and is essential for synaptic transmission. Within the brain, myelin contains the majority of cholesterol, representing 70%, with the other 30% being present in the membranes of neurons and glial cells. Disturbances in cholesterol metabolism and levels are a risk factor for developing many neurodegenerative and neurodevelopmental disorders, including schizophrenia. Schizophrenia is a psychiatric disorder with neurodevelopmental origins that is understood to result from interactions between genetic and socio-environmental factors. In the brains of patients with schizophrenia, myelin alterations and oligodendrocyte dysfunction, as well as alterations in synapse formation and a loss of synaptic connectivity have been recorded. While these functions are all supported by cholesterol metabolism under physiological conditions, the extent of the relationship between cholesterol and schizophrenia has yet to be determined. In this project, this extent will be investigated via two fronts: during neurodevelopment and in response to schizophrenia treatments. To evaluate how cholesterol metabolism may vary in schizophrenia during neurodevelopment, organoids generated from patients with schizophrenia and healthy controls will undergo several assays at three-time points, while from the other front, these assays will be carried out before and after exposure to clozapine (an antipsychotic, representing a classic treatment for schizophrenia) or cannabidiol (a recently proposed treatment option for schizophrenia). The assays that will be carried out consist of: RNAseq to obtain the expression profiles of genes involved in cholesterol metabolism; immunofluorescence to determine the expression of synaptic markers; shotgun proteomics to compare the expression of proteins involved in cholesterol metabolism; and lipidomics to visualize cholesterol levels and nearby metabolites. Our findings will expand the understanding of the neurodevelopmental mechanisms associated with schizophrenia, and provide new potential targets for drug discovery studies. (AU)