Tetratricopeptide repeat domain 9A modulates anxiety-like behavior in female mice.

Lee Wei Lim,Smeeta Shrestha,Shawn Zheng Kai Tan,Yang Sun,Chew Leng Lim,Thomas Lufkin,Sharafuddin Khairuddin,Yu Zuan Or,Hwa Hwa Chung,Valerie Chun Ling Lin

doi:10.1038/srep37568

Abstract

Tetratricopeptide repeat domain 9A (TTC9A) expression is abundantly expressed in the brain. Previous studies in TTC9A knockout (TTC9A−/−) mice have indicated that TTC9A negatively regulates the action of estrogen. In this study we investigated the role of TTC9A on anxiety-like behavior through its functional interaction with estrogen using the TTC9A−/− mice model. A battery of tests on anxiety-related behaviors was conducted. Our results demonstrated that TTC9A−/− mice exhibited an increase in anxiety-like behaviors compared to the wild type TTC9A+/+ mice. This difference was abolished after ovariectomy, and administration of 17-β-estradiol benzoate (EB) restored this escalated anxiety-like behavior in TTC9A−/− mice. Since serotonin is well-known to be the key neuromodulator involved in anxiety behaviors, the mRNA levels of tryptophan hydroxylase (TPH) 1, TPH2 (both are involved in serotonin synthesis), and serotonin transporter (5-HTT) were measured in the ventromedial prefrontal cortex (vmPFC) and dorsal raphe nucleus (DRN). Interestingly, the heightened anxiety in TTC9A−/− mice under EB influence is consistent with a greater induction of TPH 2, and 5-HTT by EB in DRN that play key roles in emotion regulation. In conclusion, our data indicate that TTC9A modulates the anxiety-related behaviors through modulation of estrogen action on the serotonergic system in the DRN.

Highlights

Mood and anxiety disorders are the most common mental illnesses with a lifetime prevalence as high as 20%1,2
Tetratricopeptide repeat domain 9A (TTC9A) was first isolated from a brain cDNA library10, and it shares significant homology with FK506 Binding Proteins (FKBP) cyclophilin 40, FKBP51, FKBP52 and FKBP38 that are steroid receptor co-chaperones involved in modulating steroid receptor assembly and maturation11,12
As serotonergic system is fundamentally important in anxiety disorders24,25, we investigated if the changes in mRNA expression levels of TPH1, TPH2, and 5-HT transporters (5-HTT) in the ventromedial prefrontal cortex (vmPFC) and the dorsal raphe nucleus (DRN) of TTC9A−/− mice would be the reason for increased anxiety-like behaviors

Summary

Introduction

Mood and anxiety disorders are the most common mental illnesses with a lifetime prevalence as high as 20%1,2. It is drastically induced by progesterone in progesterone receptor-transfected breast cancer cells MDA-MB-231 which exhibited, growth inhibition and focal adhesion in these cells; its expression is down-regulated by the estrogen in MCF7 breast cancer cells16 These data seem to suggest a negative association between TTC9A expression, cell growth and the involvement of TTC9A in ovarian steroid hormone signaling in human breast cancer cells. The anxious phenotype in TTC9A−/− mice is associated with greater induction of TPH2 and 5-HTT by EB administration that positively influences the serotonergic system These findings indicate for the first time that TTC9A modulates anxiety-related behaviors through negative regulation of estrogen action on serotonergic system in the DRN

Methods

Results

Conclusion