Title: Determining the molecular mechanisms of psychosis and developing a cellular platform for novel drug discovery: From brain to cell and back again
Funder: The Academy of Medical Sciences

Abstract: The aim of the study is to determine the molecular mechanisms underlying increased striatal dopamine synthesis capacity (DSC) in schizophrenia using midbrain organoids generated from individuals with 22q11.2 deletion and known increased DSC. We will further develop a cellular assay to assess novel targets for their ability to modulate DSC in midbrain dopaminergic neurons (mDANs) from human induced pluripotent cells (hiPSCs) and then test this model with a compound that decreases DSC. Positron Emission Tomography (PET) studies have consistently shown increased striatal DSC in schizophrenia. However, it was previously unknown if genetic risk for psychosis was associated with increased DSC. 22q11.2 deletion is the strongest genetic risk factor for psychosis, whereas the reciprocal duplication has a protective role for developing psychosis. My recent PET study was the first to show that DSC is significantly increased in 22q11.2 deletion carriers compared to 22q11.2 duplication carriers and controls. Therefore, 22q11.2 deletion represents a genetically homogenous model of increased DSC holding great potential in determining the molecular underpinnings of dopaminergic dysregulation in schizophrenia. My preliminary results showed alterations in the expression of proteins involved in dopamine metabolism in 2D mDANs from hiPSCs from 22q11.2 deletion carriers of my PET cohort. I now intend to leverage these findings by using midbrain organoids from the same hiPSCs, given their unique advantages to recapitulate the complexity of brain function. This study has the potential to identify new pharmacological targets and establish an in vitro platform to screen for potential therapeutic agents for psychosis.

Lay abstract: Previous brain imaging studies in schizophrenia have shown an increased capacity for production of a brain chemical called dopamine in a brain region called striatum. This dysfunction is present before the onset of schizophrenia and is associated with symptom severity. However, there was less evidence about whether this abnormality was present in people at high genetic risk for schizophrenia. 22q11.2 deletion is a chromosomal abnormality that increases the risk for schizophrenia more than 25% compared to the general population, whereas 22q11.2 duplication is a chromosomal abnormality that has been found to lower the risk for developing schizophrenia. Using brain scans, I recently found that that individuals with 22q11.2 deletion have increased capacity for dopamine production in the striatum compared to healthy controls and the individuals with 22q11.2 duplication. However, it remains unclear what specifically causes this increased dopamine production at the molecular level. Therefore, I decided to investigate the mechanisms underlying dopamine dysfunction by using artificially grown miniature organs resembling the brain, called brain organoids. These are created by stem cells from individuals with 22q11.2 deletion and controls that took part in my brain imaging study. I will then use these to test a novel drug in its ability to decrease the capacity for dopamine production in brain cells that produce dopamine in brain organoids. This has the potential to identify new treatments for schizophrenia.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;NEUROLOGICAL