Estrogen receptor alpha and beta regulate actin polymerization and spatial memory through an SRC-1/mTORC2-dependent pathway in the hippocampus of female mice

J Steroid Biochem Mol Biol. 2017 Nov:174:96-113. doi: 10.1016/j.jsbmb.2017.08.003. Epub 2017 Aug 5.

Abstract

Aging-related decline of estrogens, especially 17β-estradiol (E2), has been shown to play an important role in the impairment of learning and memory in dementias, such as Alzheimer's disease (AD), but the underlying molecular mechanisms are poorly understood. In this study, we first demonstrated decreases in E2 signaling (aromatase, classic estrogen receptor ERα and ERβ and their coactivator SRC-1), mTORC2 signaling (Rictor and phospho-AKTser473) and actin polymerization (phospho-Cofilin, Profilin-1 and the F-actin/G-actin ratio) in the hippocampus of old female mice compared with those levels detected in the adult hippocampus. We then showed that ERα and ERβ antagonists induced a significant decrease in SRC-1, mTORC2 signaling, actin polymerization, and CA1 spine density, as well as impairments of learning and memory; however, ovariectomy-induced changes of these parameters could be significantly reversed by treatment with ER agonists. We further showed that expression of SRC-1, mTORC2 signaling and actin polymerization could be upregulated by E2 treatment, and the effects of E2 were blocked by the ER antagonists but mimicked by the agonists. We also showed that the lentivirus-mediated SRC-1 knockdown significantly inhibited the agonist-activated mTORC2 signaling and actin polymerization, and the lentivirus-mediated Rictor knockdown also significantly inhibited the agonist-activated actin polymerization. Finally, we demonstrated that the ERα and ERβ antagonists induced a disruption in actin polymerization and an impairment of spatial memory, which were rescued by activation of mTORC2. Taken together, the above results clearly demonstrated an mTORC2-dependent regulation of actin polymerization that contributed to the effects of ERα and ERβ on spatial learning, which may provide a novel target for the prevention and treatment of E2-related dementia in the aged population.

Keywords: Actin polymerization; Estrogen receptor; Estrogens; Rictor; Spatial learning; Steroid receptor coactivator-1; mTORC2.

MeSH terms

  • Actin Depolymerizing Factors / metabolism
  • Actins / metabolism*
  • Animals
  • Aromatase / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / metabolism*
  • Estrogen Receptor beta / metabolism*
  • Estrogens / pharmacology
  • Female
  • Hippocampus / metabolism*
  • Mechanistic Target of Rapamycin Complex 2
  • Mice, Inbred C57BL
  • Multiprotein Complexes / metabolism*
  • Nuclear Receptor Coactivator 1 / genetics
  • Nuclear Receptor Coactivator 1 / metabolism
  • Ovariectomy
  • Polymerization
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Spatial Memory / physiology
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Actin Depolymerizing Factors
  • Actins
  • Carrier Proteins
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Estrogens
  • Multiprotein Complexes
  • Rapamycin-Insensitive Companion of mTOR Protein
  • rictor protein, mouse
  • Estradiol
  • Aromatase
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases