Oestradiol‐Induced Synapse Formation in the Female Hippocampus: Roles of Oestrogen Receptor Subtypes

Abstract

During the oestrus cycle, varying spine synapse density correlates positively with varying local synthesis of oestradiol in the hippocampus. In this context, the roles of the oestrogen receptor (ER) subtypes ERα and β are not fully understood. In the present study, we used neonatal hippocampal slice cultures from female rats because these cultures synthesise oestradiol and express both receptor subtypes, and inhibition of oestradiol synthesis in these cultures results in spine synapse loss. Using electron microscopy, we tested the effects on spine synapse density in response to agonists of both ERα and ERβ. Application of agonists to the cultures had no effect. After inhibition of oestradiol synthesis, however, agonists of ERα induced spine synapse formation, whereas ERβ agonists led to a reduction in spine synapse density in the CA1 region of these cultures. Consistently, up-regulation of ERβ in the hippocampus of adult female aromatase-deficient mice is paralleled by hippocampus-specific spine synapse loss in this mutant. Finally, we found an increase in spine synapses in the adult female ERβ knockout mouse, but no effect in the adult female ERα knockout mouse. Our data suggest antagonistic roles of ERβ and ERα in spine synapse formation in the female hippocampus, which may contribute to oestrus cyclicity of spine synapse density in the hippocampus.

Sexual neurosteroids and synaptic plasticity in the hippocampus

“…The latter result strongly supports the notion that in females, E2 originating from neurons is essential for synaptogenesis, rather than E2 from peripheral sources such as the ovaries (Prange-Kiel et al, 2013). The loss of synapses after inhibition of E2 synthesis in females was hippocampus-specific and was not found in the cortex and cerebellum (Zhou et al, 2010(Zhou et al, , 2014. Synapse loss was also seen specifically in the hippocampus of female, but not of male, classical ArKO mice (Zhou et al, 2014), which we used as a control for the effects after pharmacological inhibition of E2 synthesis.…”

“…Thus, ERs and also ARs, are able to induce rapid, membrane-bound effects in addition to longerlasting genomic effects. The role of membrane-bound versus genomic receptors with respect to turnover of glutamatergic synapses is highly controversial (Zhou et al, 2014). As to differences between genders in the equipment of sexual steroid receptors, it appears that AR protein expression is lower in the female hippocampus than in age-matched males (Xiao and Jordan, 2002;Feng et al, 2010) and that sex differences in the expression of estrogen receptors exist during hippocampal development (Zuloaga et al, 2013).…”

Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents

“…Two systemic injections of the ERa agonist propyl pyrazole triol (PPT) or the ERb agonist diarylpropionitrile (DPN) (Stauffer et al 2000;Meyers et al 2001) also significantly increase expression of the synaptic proteins PSD-95 and GluR1 in hippocampal CA1 (Waters et al 2009), suggesting that E 2 -induced spine increases in adult females could be mediated by either receptor. Additional support for a role of ERa comes from work with hippocampal cultures from neonatal female rats, in which 7 d of treatment with PPT significantly increased CA1 spine density (Zhou et al 2014). However, DPN significantly decreased CA1 spine density in these cultures (Zhou et al 2014), suggesting that ERb may suppress spinogenesis in early development.…”

“…Additional support for a role of ERa comes from work with hippocampal cultures from neonatal female rats, in which 7 d of treatment with PPT significantly increased CA1 spine density (Zhou et al 2014). However, DPN significantly decreased CA1 spine density in these cultures (Zhou et al 2014), suggesting that ERb may suppress spinogenesis in early development. Some data support the conclusion that input from the basal forebrain is necessary for estradiol to enhance spines in adult female rats (Leranth et al 2000).…”

Emerging roles for the novel estrogen-sensing receptor GPER1 in the CNS

“…The classical ERs, ERα and ERβ are localised to dendritic spines Milner et al, 2005;Romeo et al, 2005;Mitterling et al, 2010) and both receptor subtypes are thought to mediate the rapid effects of E2 on dendritic morphology (Sellers et al, 2015;Zhou et al, 2014;Murakami et al, 2006;Mukai et al, 2007). However recent evidence suggests that GPER1 may also play a role (Akama et al, 2013;Waters et al, 2015).…”