Thesis supervisors: Professor Eero Vasar, dr med (UT Institute of Biomedicine and Translational Medicine, Department of Physiology), Senior Research Fellow Hendrik Luuk, PhD ( Institute of Biomedicine and Translational Medicine, Department of Physiology).
Opponent: Professor Jens Randel Nyengaard, MD, DMSc (Aarhus University, Denmark).
Mood and anxiety disorders are prevalent and debilitating psychiatric disorders. Mutations in some human genes are associated with a higher incidence of these disorders. One such gene is WFS1. Homozygous mutations of WFS1 gene cause Wolfram syndrome (WS), a rare and severe disease. Although WS is characterized by multiple different symptoms like diabetes, optic nerve atrophy and deafness, WS patients also have a higher likelihood of depression, anxiety and psychoses. In addition, heterozygous carriers of WFS1 mutations display elevated chance of being hospitalized with depression. Because WFS1 mutations are closely related to debilitating psychiatric disorders, we decided to study the behavioral and biochemical phenotype caused by changes in this gene using a Wfs1-deficient mouse line. The aim was to see if the behavior and biochemical profile of these mutant mice reflects characteristics of human psychiatric disorders and would allow for this mouse model to be used when screening anxiolytic and antidepressant drugs in the field of translational medicine. In addition, we wanted to know which kind of biochemical changes accompany Wfs1 deficiency in neurotransmitter systems (dopamine, serotonin, noradrenaline, GABA) strongly implicated in psychiatric disorders. We first found that these mice had alterations to serotonin metabolism and an elevated reaction to serotonergic antidepressants in behavioral despair experiments. At the same time, brain serotonin levels do not rise in Wfs1-deficient animals in response to exposure to a stress-inducing environment. By contrast, serotonin levels do rise in wild-type animals which is a known response. Secondly, the dopaminergic system is impaired in many aspects in Wfs1 mutants. Thirdly, we detected behavioral and genetic alterations to the GABA system, owing to Wfs1 gene deficiency, which indicate changes to mechanisms important in the etiology of anxiety.