Estrogen receptor alpha and beta specific agonists regulate expression of synaptic proteins in rat hippocampus

Abstract

Changes in hippocampal CA1 dendritic spine density and synaptic number across the estrous cycle in female rats correlate with increased hippocampal-dependent cognitive performance in a manner that is dependent on estrogen receptors (ERs). Two isoforms of the estrogen receptor, α and β are present in the rat hippocampus and distinct effects on cognitive behavior have been described for each receptor. The present study generated a profile of synaptic proteins altered by administration of estradiol benzoate, the ERα selective agonist PPT (1,3,5-tris (4-hydroxyphenyl)-4-propyl-1H-pyrazole) and the ERβ selective agonist DPN (2,3-bis (4-hydroxyphenyl) propionitrile) alone and in combination in comparison to vehicle in the CA1 region of the dorsal hippocampus. In the stratum radiatum, estradiol, DPN, and PPT increased PSD-95 and AMPA-type glutamate receptor subunit GluR1. Only DPN administration regulated expression of AMPA receptor subunits GluR2 and GluR3, increasing and decreasingly levels respectively. DPN also increased GluR2 expression in the other lamina of the CA1. These results support previous reports that estradiol and isoform specific agonists differentially activate ERα and ERβ to regulate protein expression. The distinct effects of DPN and PPT administration on synaptic proteins, suggest that the desired therapeutic outcome of estrogen may be accomplished by using specific estrogen receptor agonists. Moreover, the effects of estradiol treatment on PSD-95 expression are consistent with a growing body of evidence that this postsynaptic protein is a key marker of estrogen action related to spine synapse formation.

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

“…Two systemic injections of estradiol benzoate given 24 h apart fully reversed this decrease within 48 h (although a significant increase was seen within 24 h), and an injection of progesterone 48 h later augmented the effects of estradiol on spines within the first 10 h of treatment (Woolley and McEwen 1993). 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).…”

Developmental expression of genes involved in neural estrogen biosynthesis and signaling in the brain of the orange-spotted grouper Epinephelus coioides during gonadal sex differentiation

“…Further, estrogen has been reported to be essential for female gonadal differentiation [33,34] and sex change [35,36] in teleosts. Molecular cloning and identification of differential expression patterns of the different forms of the estrogen receptor (ER˛, ERˇ1, and ERˇ2 or ER ) during early development and adult stages have been reported in a number of vertebrate species [37][38][39] including fish [40][41][42]. In addition, ERs are highly expressed during ovarian differentiation in tilapia (Oreochromis niloticus), rainbow trout (Oncorhynchus mykiss) and black porgy [34,43,44], suggesting reproductive roles for ERs in sex differentiation in fish species.…”

Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus

“…In rodents and nonhuman primates, E 2 increases hippocampal levels of synaptic proteins, including the presynaptic proteins synaptophysin and syntaxin, and the postsynaptic proteins spinophilin and PSD-95 (Brake et al 2001;Frick et al 2002;Choi et al 2003;Spencer et al 2008;Waters et al 2009). E 2 also significantly increases hippocampal CA1 dendritic spine density in rodents and nonhuman primates McEwen 1992, 1993;Hao et al 2003;Frick et al 2004).…”