Cellular and Functional Characterization of Schizophrenia iPSC-derived Microglia

• Grant number: 23/08885-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): March 01, 2024
• Effective date (End): July 31, 2027
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Daniel Martins-de-Souza
• Grantee: Aline Valéria Sousa Santos
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 17/25588-1 - From the basic understanding to clinical biomarkers to schizophrenia: a neuroproteomics-centered multidisciplinary study, AP.TEM

Abstract

Schizophrenia is a severe and debilitating mental disorder characterized by positive, negative, and cognitive symptoms with a prevalence of approximately 1% of the world's population. It has a complex etiology involving a multifactorial interaction between genetic and environmental risk factors. While the exact causes of schizophrenia are still unclear, there is growing evidence that neuroinflammation plays a critical role in the development, progression, and onset of the disorder. Epidemiological data have implicated maternal infection during pregnancy as a risk factor for the later development of schizophrenia in offspring, indicating the potential impact of prenatal immune challenges on brain development. These alterations can disrupt normal neurodevelopmental processes, leading to long-term changes in brain circuitry and increased vulnerability to psychiatric disorders, including schizophrenia, which can be triggered by other stressors, such as drug exposure at a vulnerable age.The present work aims to investigate the relationship between neuroinflammation and schizophrenia, using microglial cells, the central nervous system resident immune cell, derived from schizophrenia patients, and their possible role in the pathophysiology of this disorder. To this end, we will establish a protocol for the differentiation of human-derived induced pluripotent stem cells derived from schizophrenia patients, as well as healthy control, into microglia cells, and perform a complete characterization of the cellular and functional phenotype. This project proposes to establish a 'first hit' in vitro model to investigate the effects of immunological challenges at critical developmental stages on cells from schizophrenia patients compared to healthy controls, including evaluation of the shotgun proteomic signature of these cells. We will further compare the susceptibility of differentiated microglia cells to an immune challenge at the mature stage, evaluating the modulation in immune-related gene expression and the microglia-released molecular profile, by lipidomic analysis. Additionally, we will access the synaptic phagocytic activity, in a neuron-microglia co-culture system, a well-described schizophrenia-related finding. With this study, we hope to contribute to well-informed decision-making in future investigations related to the relationship between inflammation and schizophrenia.