TTC9A deficiency induces estradiol-mediated changes in hippocampus and amygdala neuroplasticity-related gene expressions in female mice

Brain Res Bull. 2020 Apr:157:162-168. doi: 10.1016/j.brainresbull.2020.02.004. Epub 2020 Feb 10.

Abstract

The involvement of tetratricopeptide repeat domain 9A (TTC9A) deficiency in anxiety-like responses and behavioral despair through estradiol action on the serotonergic system has been reported. Emerging evidence suggests that estradiol is a potent modulator of neuroplasticity. As estradiol and neuroplasticity changes are both implicated in mood regulation, and estradiol activity is negatively regulated by TTC9A, we hypothesized that the behavioral changes induced by Ttc9a-/- is also mediated by neuroplasticity-related mechanisms. To understand the effects of TTC9A and estradiol modulation on neuroplasticity functions, we performed a behavioral analysis of tail suspension immobility and neuroplasticity-related gene expression study of brain samples collected in a previous study involving ovariectomized (OVX) Ttc9a-/- mice with estradiol or vehicle treatment. We observed that OVX-Ttc9a-/- mice had significantly reduced the tail suspension immobility compared to OVX-Ttc9a-/- estradiol-treated mice. Interestingly, there was an upregulation in gene expression of tropomyosin receptor kinase B (Trkb) in the ventral hippocampus, as well as brain-derived neurotrophic factor (Bdnf) and postsynaptic density protein-95 (Psd-95) in the amygdala of OVX-Ttc9a-/- mice compared to those treated with estradiol. These findings indicate that estradiol plays an inhibitory role in neuroplasticity in Ttc9a-/- mice. These observations were not found in the wildtype mice, as the presence of TTC9A suppressed the effects of estradiol. Our data suggest the behavioral alterations in Ttc9a-/- mice were mediated by estradiol regulation involving neuroplasticity-related mechanisms in both the hippocampus and amygdala regions.

Keywords: Amygdala; Estradiol; Hippocampus; Neuroplasticity; Tetratricopeptide repeat domain 9A (TTC9A).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / metabolism
  • Animals
  • Anxiety / drug therapy*
  • Anxiety / metabolism
  • Estradiol / pharmacology*
  • Estrogens / pharmacology
  • Female
  • Gene Expression / drug effects
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Neuronal Plasticity / drug effects*

Substances

  • Estrogens
  • Nerve Tissue Proteins
  • Estradiol