Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Ruben van Vugt (Donders series 536)

29 March 2022

Promotor: Prof. dr. E.J.M. Storkebaum
Co-promotor: Dr. G.J.V. Poelmans

Stress in schizophrenia: from rats to molecules

In the past years, multiple hypotheses about the etiological factors underlying schizophrenia (SZ) have been proposed. In this thesis we used hypothesis-generating techniques at the genomic and proteomic levels to identify the molecular mechanisms underlying the SZ-like behavior in apomorphine-susceptible (APO-SUS) rats model, a model for SZ, and their phenotypically normal counterparts, apomorphine-unsusceptible (APO-UNSUS) rats. This animal model was developed using behavioral selection based on their gnawing score (which indicates stereotypic behavior, a symptom of SZ) for multiple generations, which opens up the opportunity of an unbiased analysis of the molecular factors involved in the model. The data collected in these two studies were used to create so-called ‘molecular landscapes’ that show the relation between the identified genes/proteins and their role within mo-lecular pathways involved in the disease. Both landscapes are located in neurons and oligodendrocytes (ODCs) and are involved in the formation of myelin by ODCs/ There is ample previous evidence that disturbances of myelin synthesis and function are involved in SZ. The landscape from the GWAS also contains and adrenal cortex cell, indicating a role for the HPA-axis (stress-axis), whereas the proteomic landscape showed that oxidative stress plays a role in the development of the phenotype.
Additionally, we studied the levels of multiple metabolites in the blood and cerebrospinal fluid (CSF) in SZ patients. We used a polygenic risk score-based approach to screen for the presence and extent of genetic sharing between SZ and the (increased or decreased) levels of these metabolites. Among the metabolites that showed genetic sharing with SZ were those involved in processes that have been previously linked to SZ.
Additionally, we performed a more in-depth analysis of the Mc2r gene identified in the GWAS in this thesis. In silico analysis, in addition to a bio-assay on adrenal cells indicate that the missense mutation in Mc2r that is associated with SZ-like behavior has a modulatory effect on the increased stress response of APO-SUS rats.
Lastly, using a cross-fostering study, we found that APO-SUS mothers provided less appropriate maternal care as compared to APO-UNSUS mothers. This led to more SZ-like behavior in the APO-UNSUS pups fostered by APO-SUS mothers as compared to the pups fostered by APO-UNSUS mothers.
All the studies in this thesis were performed with the goal of conducting an extensive analysis of the genetic background of SZ. Interestingly, the different analyses performed all indicated a role for some type of stress in the etiology of the disease, namely environmental stress, oxidative stress, and perinatal stress.