Topoisomerase IIIβ Deficiency Induces Neuro-Behavioral Changes and Brain Connectivity Alterations in Mice.

Faiz Ur Rahman,Won-Kee Yoon,Mi-Ni Lee,Hyoung-Chin Kim,Chin-Soo Lee,Ki-Hoan Nam,Sang-Mi Cho,Seul Gi Park,Kimi Araki,Eun-Kyeung Kim,Su Jin Kim,Young-Suk Won,Kihoon Lee,Ken-Ichi Yamamura,Hae-Rim Kim,Younghee Lee,Ho-Young Lee,You-Rim Kim

doi:10.3390/ijms222312806

Abstract

Topoisomerase IIIβ (Top3β), 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 Top3β with neuropsychiatric phenotypes in mice. Here, we investigated the effect of Top3β on neuro-behavior using newly generated Top3β deficient (Top3β−/−) mice. We found that Top3β−/− mice showed decreased anxiety and depression-like behaviors. The lack of Top3β was also associated with changes in circadian rhythm. In addition, a clear expression of Top3β 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 Top3β−/− 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 Top3β is essential for normal brain function and behavior in mice and that Top3β could be an interesting target to study neuropsychiatric disorders in humans.

Highlights

IntroductionDNA topoisomerases are “magicians of the DNA world”
RT-PCR analysis showed that topoisomerase 3β (Top3β) mRNA was undetectable in brains, livers, and spinal cords from Top3β−/− mice
In the observation using an indirect calorimeter equipped with sensors for activity measurement, both male and female Top3β−/− mice showed decreased total movement during a dark time compared to WT mice (Figure 4A,B) there was no change in circadian rhythm, the sleep/wake cycle. Both male and female Top3β−/− mice showed increased water intake during a light time compared to WT mice (Figure 4C,D). These results suggest that Top3β deficiency affects anxiety/depression-related behaviors, and disrupts circadian activities during light and dark time periods of a day in mice

Summary

Introduction

DNA topoisomerases are “magicians of the DNA world” They are ubiquitous enzymes that can control topological problems associated with DNA replication, transcription, recombination, and chromatin remodeling by incorporating transient single- or doublestrand breaks into DNA [1,2,3]. Of all members of the DNA topoisomerase family, topoisomerase 3β (Top3β) is the newest member identified both in humans and mice [5,6]. This type 1A topoisomerase has been found to have dual activities, capable of changing the topology of both DNA and RNA in animals [7]. Emerging evidence has shown that mutations in the TOP3β gene contribute to neurodevelopmental disorders associated with schizophrenia and cognitive defects in humans [8]. In distal deletion syndrome characterized by mental retardation and cognitive dysfunction, TOP3β is frequently deleted in the 22q11.2 [15]

Methods

Results

Discussion

Conclusion