Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand

Xin Jie Tan, Yu Bing Dai, Wan Fu Wu, Hyun Jin Kim, Rodrigo P.A. Barros, Timothy I. Richardson, Benjamin C. Yaden, Margaret Warner, David L. McKinzie, Venkatesh Krishnan, Jan Åke Gustafsson

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44 Scopus citations


An estrogen receptor (ER) β ligand (LY3201) with a preference for ERβover ERα was administered in s.c. pellets releasing 0.04 mg/d. The brains of these mice were examined 3 d after treatment had begun. Although estradiol-17β is known to increase spine density and glutaminergic signaling, as measured byGolgi staining, a clear reduction in spines was evident on the dendritic branches in LY3201-treated mice but no morphological alteration and no difference in the number of dendritic spines on dendritic stems were observed. In the LY3201-treatment group, there was higher expression of glutamic acid decarboxylase (GAD) in layer V of cortex and in the CA1 of hippocampus, more GAD + terminals surrounding the pyramidal neurons and less glutamate receptor (NMDAR) on the neurons in layer V. There were no alterations in expression of Iba1 or in Olig2 or CNPase. However, GFAP + astrocytes were increased in the LY3201-treatment group. There were also more projections characteristic of activated astrocytes and increased expression of glutamine synthetase (GS). No expression of ERβ was detectable in the nuclei of astrocytes. Clearly, LY3201 caused a shift in the balance between excitatory and inhibitory neurotransmission in favor of inhibition. This shift was due in part to increased synthesis of GABA and increased removal of glutamate from the synaptic cleft by astrocytes. The data reveal that treatment with a selective ERβ agonist results in changes opposite to those reported in estradiol-17β-treated mice and suggests that ERα and ERβ play opposing roles in the brain.

Original languageEnglish (US)
Pages (from-to)1708-1712
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
StatePublished - Jan 31 2012


  • Cerebral cortex
  • Glutamate toxicity
  • Hippocampus
  • Neurotransmitter

ASJC Scopus subject areas

  • General


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