Estrogens facilitate memory processing through membrane mediated mechanisms and alterations in spine density

Abstract

Estrogens exert sustained, genomically mediated effects on memory throughout the female life cycle, but here we review new studies documenting rapid effects of estradiol on memory, which are exerted through membrane-mediated mechanisms. Use of recognition memory tasks in rats shows that estrogens enhance memory consolidation within 1h. 17α-Estradiol is more potent than 17β-estradiol, and the dose response relationship between estrogens and memory is an inverted U shape. Use of specific estrogen receptor (ER) agonists suggests mediation by an ERβ-like membrane receptor. Enhanced memory is associated with increased spine density and altered noradrenergic activity in the medial prefrontal cortex and hippocampus within 30 min of administration. The environmental chemical, bisphenol-A, rapidly antagonizes enhancements in memory in both sexes possibly through actions on spines. Thus, estradiol and related compounds exert rapid alterations in cognition through non-genomic mechanisms, a finding which may provide a basis for better understanding and treating memory impairments.

Figure 1

Schematic of genomic mechanism for estrogenic responses and effects of estradiol and receptor agonists on recognition memory. Circulating estrogens enter the cell nucleus where they bind to two types of receptors, ERα and ERβ, and the complex acts as a nuclear transcription factor by binding to an estrogen response element (ERE) on DNA and stimulating transcription of specific genes whose proteins then alter neural functions including the enhancement of memory. A: Estradiol enhances memory. EB was given at 50ug/kg for 2 days and object recognition and placement tested 48 hours later, P < 0.001. B. Effects of specific ER agonists on object recognition. ERα specific agonist, PPT, and ERβ specific agonists, C19 and DPN, were given as in Inset A. Only ERβ agonists enhanced memory, p < 0.05. Data from [49].

Figure 2

Schematic for non-genomic mechanism for estrogenic responses and effects of estrogens, estrogen receptor agonists and D-R relationship. Circulating estrogens bind at cell membrane receptors to initiate rapid “non -genomic” mechanisms at the membrane surface and thereby bypass the nuclear EREs and instead activate intracellular signaling cascades and immediately early genes which initiate rapid memory enhancements. Membrane ER α and βs have been identified as well as others not as well described (ER?). A. 17α and β-estradiol enhance memory. When given 30 min prior to a sample trial, both isomers of estradiol enhance object recognition memory 4 h later. Data from [70]. B. Dose-response curve for 17β-estradiol and object placement. Given immediately following the sample trial and retention testing 4 h later, the D-R curve is an inverted U with 20ug/kg the only effective dose. Data from [47]. C. Effect of ER agonists on object recognition. Given immediately following the sample trial and retention testing 4 h later, only the ERβ agonist, DPN, enhanced memory. Data from [49]. Abbreviations: ERK, extracellular signal-regulated kinase; CREB, cAMP response element binding protein; CRE, cAMP response element. Data from[49].

Figure 3

Depiction of recognition memory tasks. A rat is shown on the open field with objects.

Figure 4

Timeline for memory consolidation and effects of DES given before and after sample trial on consolidation. Work by McGaugh [80] has shown that memories are consolidated during the first 1-2 hours following a sample or training trial. Drug or hormone treatments can enhance or impair memory during this window for treatment even when retention is tested up to 48 hours later. If treatments are given later than 2 h post T1, they do not affect memory consolidation. A. DES, 15 ug/kg, was given 30 min before T1, and object recognition was enhanced 4 h later. B. DES, 15 ug/kg, was given immediately after T1, and object recognition was enhanced 4 h later. C. DES, 15 ug/kg, was given 2h after T1, and object recognition was not enhanced 4 h later. ** P < 0.01. Data from [70]

Figure 5

BPA impairs recognition memory in male and female rats. A. Male rats. BPA was given immediately following T1 at 40 ug/kg and Object and Place recognition was tested 4 h later and expressed as % time with new object/place. * P < 0.05. Data from Eilam-Stock and Luine, unpublished. B. Female Rats. BPA was given 30 min before T1 at 40 ug/kg, estradiol was given immediately following T1 at 5 ug/kg for object memory and 20 ug/kg for place memory, retention was tested 4 h after T1. ** P < 0.01. Data from [48].

Figure 6

Golgi impregnated pyramidal cells in the brain of an adult female rat. A. Medial prefrontal cortex. Cells are shown at 10x magnification. Layer ll/lll pyramidal cells are used in our analyses. Adapted from [68]. B. CA1 of the hippocampus. The photomicrograph is at 40x magnification. Frankfurt, unpublished.

Figure 7

Rapid effects of 17β-estradiol and BPA on spine density A. Golgi impregnated secondary basal dendrite from a CA1 neuron illustrating dendritic spines (arrows). Scale bar = 20μm. Adapted from [68]. B. Estradiol rapidly increases spine density in adult female rats. OVX female rats were given a recognition memory sample trial and then were immediately injected with vehicle or 20μg/kg 17 β-estradiol. Subjects were sacrificed 30 min after the T1 trial and spine was density measured. * P< 0.05, ** P < 0.01. Data from [48]. C. BPA rapidly decreases spine density in adult male rats. Males were given a recognition memory sample trial and then were immediately injected with vehicle or 40 ug/kg BPA. Subjects were sacrificed 30-40 min after the T1 trial. * P< 0.05, ** P < 0.01. CA3 data unpublished by Restrepo and Luine, other areas from [20].