Rapid Effects of Estrogen Receptor α and β Selective Agonists on Learning and Dendritic Spines in Female Mice

Abstract

Estrogen receptor (ER) agonists rapidly affect neural plasticity within 1 h, suggesting they play a functional role in learning and memory. However, behavioral learning experiments on such a rapid time scale are lacking. Therefore we investigated whether the ER␣ agonist propyl pyrazole triol (PPT) and ER␤ agonist diarylpropionitrile (DPN) could affect social recognition, object recognition, or object placement learning within 40 min of drug administration. At the same time, we examined their effects on CA1 hippocampal dendritic spines. Ovariectomized female CD1 mice were administered a range of PPT or DPN doses (0,30,50, 75, or 150 g/mouse). PPT at the middle doses improved social recognition, facilitated object recognition and placement at a dose of 75 g, and increased dendritic spine density in the stratum radiatum and lacunosum-moleculare. In contrast, DPN impaired social recognition at higher doses, did not affect object recognition, but slightly facilitated object placement learning at the 75-g dose. DPN did not affect spines in the stratum radiatum but decreased spine density and increased spine length in the lacunosum-moleculare. This suggests that rapid estrogenmediated learning enhancements may predominantly be mediated through ER␣, while the effects of DPN are weaker and may depend on the learning paradigm. The role of ER␣ and ER␤ in learning and memory may vary depending on the timing of drug administration, as genomic studies often implicate ER␤ in enhancing effects on learning and memory. To our knowledge, this is the first report of estrogens' effects on learning within such a short time frame. (Endocrinology 152: 1492-1502, 2011) E strogens affect many physiological and behavioral processes including reproduction, feeding, mood, and learning and memory (see 1). The classical mechanism of action for intranuclear estrogen receptors (ER), ER␣ and ER␤, is to regulate transcription of target genes, requiring hours to affect protein expression (reviewed in Ref. 2). However, estrogens also have nongenomic actions initiated at the cell membrane that influence cell signaling cascades within minutes (reviewed in Ref. 3). While there are many studies on estrogens' genomic effects, their rapid, nongenomic effects and the functional behavioral implications thereof are not well understood.The natural estrogen, 17␤-estradiol, rapidly modulates cell signaling, synaptic transmission, and dendritic spine density within 1 h of administration. Signaling cascades (4 -7) and excitatory transmission (4, 8 -10) were enhanced in cultured neurons or hippocampal sections within 30 min of 17␤-estradiol or estradiol benzoate application. 17␤-estradiol facilitated long-term potentiation (8,11, but see Ref. 12), affected long-term depression (12, 13), and rapidly increased dendritic spine density and synapse number as quickly as 15 min after drug application, thereby enhancing neuronal connections in brain regions critical for learning and memory (6,12,14,15). Thus estrogens rapidly modulate synaptic plasticity in a way that s...

Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements

“…S1). However, it is unlikely that this higher investigation duration indicates an enhanced interest in objects that then leads to a facilitation of object recognition learning, because this effect was not found in the object placement paradigm, in PPT experiments, or during systemic experiments (2,3). Therefore, we conclude that intrahippocampal delivery of 17β-estradiol, via ERα, rapidly and specifically enhances learning and memory.…”

“…Because systemic estrogen administration previously induced learning and memory enhancements, we used tasks with reduced learning opportunities (Fig. 1A) such that vehicle controls do not display discrimination of the novel stimulus at test (3). Effects of treatment on investigation durations and other behavioral measures were recorded and are discussed below.…”

“…immature synapse | short-term memory | structural plasticity | synaptic plasticity | signal-to-noise ratio E stradiol rapidly and dramatically increases hippocampal dendritic spine and synapse density within minutes of application (1)(2)(3)(4). There is a strong correlative association between estrogeninduced spinogenesis and improvements in cognition (5); however, the relationship of these structural changes to estrogen-induced alterations in hippocampal function is unclear.…”

“…There is a strong correlative association between estrogeninduced spinogenesis and improvements in cognition (5); however, the relationship of these structural changes to estrogen-induced alterations in hippocampal function is unclear. Our laboratory recently reported that the density of hippocampal CA1 pyramidal dendritic spines increases very rapidly after systemic treatment with 17β-estradiol or estrogen receptor (ER) -selective agonists in ovariectomized female mice, changes that are paralleled by learning enhancements (2,3). Estrogen-induced rapid structural changes are substantial, increasing spine density by 30-50% within 15-40 min of hormone application (1)(2)(3)6).…”

“…Our laboratory recently reported that the density of hippocampal CA1 pyramidal dendritic spines increases very rapidly after systemic treatment with 17β-estradiol or estrogen receptor (ER) -selective agonists in ovariectomized female mice, changes that are paralleled by learning enhancements (2,3). Estrogen-induced rapid structural changes are substantial, increasing spine density by 30-50% within 15-40 min of hormone application (1)(2)(3)6). As a result, adult rodents can experience the addition of thousands of CA1 synapses within a span of minutes after exposure to estradiol.…”