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

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.