Topoisomerase III beta Deficiency Induces Neuro-Behavioral Changes and Brain Connectivity Alterations in Mice

Topoisomerase III beta (Top3 beta), the only dual-activity topoisomerase in mammals that can change topology of both DNA and RNA, is known to be associated with neurodevelopment and mental dysfunction in humans. However, there is no report showing clear associations of Top3 beta with neuropsychiatric phenotypes in mice. Here, we investigated the effect of Top3 beta on neuro-behavior using newly generated Top3 beta deficient (Top3 beta(-/-)) mice. We found that Top3 beta(-/-) mice showed decreased anxiety and depression-like behaviors. The lack of Top3 beta was also associated with changes in circadian rhythm. In addition, a clear expression of Top3 beta was demonstrated in the central nervous system of mice. Positron emission tomography/computed tomography (PET/CT) analysis revealed significantly altered connectivity between many brain regions in Top3 beta(-/-) mice, including the connectivity between the olfactory bulb and the cerebellum, the connectivity between the amygdala and the olfactory bulb, and the connectivity between the globus pallidus and the optic nerve. These connectivity alterations in brain regions are known to be linked to neurodevelopmental as well as psychiatric and behavioral disorders in humans. Therefore, we conclude that Top3 beta is essential for normal brain function and behavior in mice and that Top3 beta could be an interesting target to study neuropsychiatric disorders in humans.