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

Abstract

Dramatic increases in hippocampal spine synapse density are known to occur within minutes of estrogen exposure. Until now, it has been assumed that enhanced spinogenesis increased excitatory input received by the CA1 pyramidal neurons, but how this facilitated learning and memory was unclear. Delivery of 17β-estradiol or an estrogen receptor (ER)-α (but not ER-β) agonist into the dorsal hippocampus rapidly improved general discrimination learning in female mice. The same treatments increased CA1 dendritic spines in hippocampal sections over a time course consistent with the learning acquisition phase. Surprisingly, estrogen-activated spinogenesis was associated with a decrease in CA1 hippocampal excitatory input, rapidly and transiently reducing CA1 AMPA activity via a mechanism likely reflecting AMPA receptor internalization and creation of silent or immature synapses. We propose that estrogens promote hippocampally mediated learning via a mechanism resembling some of the broad features of normal development, an initial overproduction of functionally immature connections being subsequently "pruned" by experience.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 (1-4). 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. 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 (1-3, 6). As a result, adult rodents can experience the addition of thousands of CA1 synapses within a span of minutes after exposure to estradiol. These effects of estrogens reproduce the changes occurring during the 4-d estrous cycle of female rodents, which include the induction of CA1 spines (7).How these processes contribute to the behavioral changes observed after estradiol treatment is not understood. Estradiol enhances excitatory neurotransmission throughout the hippocampus (8-10), and activates BDNF signaling in the mossy fiber system (11). Dendritic spines turn over more rapidly in the hippocampus than in the neocortex (12), particularly in the case of estradiol-induced spines (13). Such rapid, transient, and apparently indiscriminate increases in excitatory synapse formation would seem, at first sight, to be more likely to interfere with preexisting brain circuits and impair normal information processing than to enhance cognitive function.How then, does enhancement of spine formation lead to improved ...

Estrogen enhances hippocampal gray-matter volume in young and older postmenopausal women: a prospective dose-response study

“…Estrogen has been shown to increase the density of dendritic spines on CA1 pyramidal neurons especially following neuronal damage or estrogen loss (Woolley, 1998; Woolley and McEwen, 1992) while estrogen receptor antagonists block this effect (Lewis et al, 1995). The presence of estrogen appears to prime the neuron for new synapse creation through an increase in dendritic spines, however these new spines are only maintained following synapse activation (Phan et al, 2015). …”

Why estrogens matter for behavior and brain health

“…In behaviorally naïve ovariectomized female mice, it was also found that systemic treatment with 17β-estradiol (Phan et al, 2012), ERα agonist PPT (Phan et al, 2011) and GPER agonist G1 (Gabor, Lymer et al, 2015) rapidly increased dendritic spine density in CA1 field of the hippocampus, while ERβ agonist DPN decreased it (Phan et al, 2011). Subsequently, it was shown that bath application of 17β-estradiol and ERα agonist PPT for 20–30 minutes to hippocampal sections from behaviorally naïve postnatal female (PND 20–32) mice enhanced dendritic spine density (Phan et al, 2015). Intriguingly, within the same timeframe as the dendritic spines and learning enhancements, 17β-estradiol also decreased CA1 hippocampal excitatory input, rapidly and transiently reducing AMPA responses, likely through AMPA receptor internalization (see Figure 2A; Phan et al, 2015).…”

“…Subsequently, it was shown that bath application of 17β-estradiol and ERα agonist PPT for 20–30 minutes to hippocampal sections from behaviorally naïve postnatal female (PND 20–32) mice enhanced dendritic spine density (Phan et al, 2015). Intriguingly, within the same timeframe as the dendritic spines and learning enhancements, 17β-estradiol also decreased CA1 hippocampal excitatory input, rapidly and transiently reducing AMPA responses, likely through AMPA receptor internalization (see Figure 2A; Phan et al, 2015). Hence, it appears new spines induced by estrogens are associated with silent or immature synapses.…”

“…Infusion of 17β-estradiol or the ERα agonist PPT (Phan et al, 2015) into the dorsal hippocampus rapidly improved performance in social recognition, object recognition, and object placement tasks, while the ERβ agonist DPN was ineffective. Similarly, infusion of the GPER agonist G1 enhanced social and object recognition but did not affect object location recognition in the object placement task (Lymer et al, submitted).…”

Rapid actions of oestrogens and their receptors on memory acquisition and consolidation in females

“…However, in most cases, pre‐acquisition treatment will affect subsequent phases, especially consolidation, because the treatment and/or its downstream products/effects will remain active during this phase. Therefore, to study effects on acquisition, tasks are commonly designed such that testing occurs immediately after learning and/or before consolidation is complete [Lymer JM, Sheppard PAS, Kuun T, et al Estrogens and their receptors in the medial amygdala rapidly promote social recognition in female mice (unpublished)] or results from pre‐ and post‐acquisition treatments are compared. If pre‐acquisition, but not post‐acquisition, treatment affects memory, this would suggest a treatment effect on acquisition but not consolidation.…”