Schizophrenia risk factor Tcf4 and gene-environment interaction in mice

by Dorota Badowska
Doctoral thesis
Date of Examination:2014-11-03
Date of issue:2015-02-23
Advisor:PD Dr. Moritz Rossner
Referee:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. André Fischer
Referee:Prof. Dr. Michael Hoerner
Referee:Prof. Dr. Mikael Simons
Persistent Address: http://dx.doi.org/10.53846/goediss-4943

 

 

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Abstract

English

Psychiatric diseases are triggered by the interaction of genetic and environmental risk factors (GxE). To model GxE in mice, we developed an approach to analysing huge behavioural data sets, which allowed us to compare mice tested in independent cohorts. In a battery of tests, we analysed and compared mice subjected to Isolation rearing (IR), Social defeat (SD) or the control condition Enriched environment (EE). By using multivariate statistics, we merged experiments measuring similar behaviours into higher-order categories (dimension reduction). This allowed us to create clinically relevant behavioural profiles of mice and visualise them in a single radar chart. We show that IR as a paradigm models positive symptoms of psychotic diseases, while SD models negative-like symptoms. We used this approach to study GxE in transgenic mice overexpressing the schizophrenia risk gene Tcf4. They displayed deficits in fear memory and behavioural flexibility upon IR and SD, while EE rescued the phenotype. Ageing did not influence these impairments. This result points at the role of Tcf4 in cognition. Tcf4 overexpressing mice also displayed enhanced LTD in hippocampus as well as increased dendritic spine frequency and upregulation of proteins: CaMKII, HOMER1 and synaptobrevins in prefrontal cortex. RNA sequencing revealed deregulation of BC1, Top3b and Mov10 involved in regulation of translation by microRNAs, and other genes, e.g. Adora2a, Penk and Plxna1. We also tested behaviour of Tcf4-/+ mice, which showed strong cognitive impairment specific to hippocampus-dependent spatial learning. Analysis of Tcf4 expression in these mice revealed downregulation mainly of the isoforms that are highly expressed in the hippocampus, which is in line with the behavioural phenotype. We conclude that in mice Tcf4 is important predominantly for cognition, which declines upon both overexpression and deficiency of the gene. In the last project, we focused on mechanisms underlying pain insensitivity, which we observed in the IR animals. We show that IR reduces expression of pronociceptive genes Vgf, Bdnf and Npyr1 in dorsal root ganglia, which may contribute to pain insensitivity. In hypothalamus, IR reduced expression of oxytocin and arginine vasopressin, potentially adding to the pain phenotype as well as to IR-induced aggressiveness.
Keywords: schizophrenia; gene-environment interaction; Tcf4; mouse models; social isolation; social defeat; behaviour; pain sensitivity
 
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