Estrogen Receptor Gene Polymorphisms Research Articles

Association of estrogen receptor genes and schizophrenia: A preliminary study

Gender differences in various clinical features of schizophrenia have been noted and estrogen has been regarded to play important roles. A few previous studies on the association between estrogen receptor (ER) genotypes and schizophrenia focused mainly on ER α gene but failed to report consistent results. The present study was designed to analyze the differences in the frequencies of both ERα and ERβ gene polymorphisms in subjects with schizophrenia compared to healthy controls among Korean population. Moreover, we investigate the association between different genotypes of ER genes and various clinical variables of schizophrenia. We observed that PvuII and XbaI polymorphisms of ERα gene showed significant differences between patients with schizophrenia and control groups (p=0.006). Among clinical variables, only the age of onset was related to RsaI genotype of ERβ gene (p=0.039). In conclusion, the present study suggests that ERα gene polymorphisms may be associated with the pathogenesis of schizophrenia and RsaI AA genotype of ERβ might have protective effect on age at onset of schizophrenia in Korean patients with schizophrenia.

Association between estrogen receptor alpha gene polymorphisms and bone mineral density in Polish female patients with Graves' disease.

Graves' (GD) hyperthyroidism leads to reduced bone mineral density (BMD) accompanied by accelerated bone turnover. Ample studies have identified association between estrogen receptor (ESR1) gene polymorphism and decreased BMD and osteoporosis. In contrast, number of publications that link ESR1, BMD and Graves' disease is limited. The purpose of this study was to identify the association between ESR1 polymorphisms and BMD in premenopausal women with GD and to determine whether ESR1 polymorphic variants can predispose to GD. The study included 75 women aged 23-46 years with GD and 163 healthy controls. BMD was measured at lumbar spine and femoral neck. We investigated two SNPs in the ESR1 gene and analyzed genetic variants in the form of haplotypes reconstructed by statistical method. Three out of four possible haplotypes of the PvuII and XbaI restriction fragment length polymorphisms were found in GD patients: px (55.3 %), PX (33.3 %) and Px (11.4 %). Women homozygous for xx of XbaI and for pp of PvuII had the lowest BMD at lumbar spine. Moreover, the px haplotype predisposed to reduced lumbar BMD. No associations were observed for femoral neck BMD. No statistically significant relationship were found between ESR1 polymorphisms or their haplotypes and GD. These results indicate that the PvuII and the XbaI polymorphisms of ESR1 gene are associated with bone mineral density in premenopausal women with GD and may help to estimate the risk of bone loss particularly at lumbar spine. However, none of the ESR1 gene alleles predict the risk of GD in Polish female patients.

Replication study of the association between adolescent idiopathic scoliosis and two estrogen receptor genes

Adolescent idiopathic scoliosis (AIS) is a common disorder with a strong genetic predisposition. Associations between AIS and common single nucleotide polymorphisms (SNPs) in estrogen receptor genes have been reported. rs9340799 in the gene for estrogen receptor α (ESR1) is reported to be associated with curve severity in Japanese and with AIS predisposition and curve severity in Chinese. In addition, rs1256120 in the gene for estrogen receptor β (ESR2) is reported to be associated with AIS predisposition and curve severity in Chinese. However, the sample sizes of these previous studies were small, and the associations of these SNPs have not been replicated. To examine the association between AIS and estrogen receptor genes, we investigated the association of rs9340799 and rs1256120 with AIS predisposition and curve severity using a large Japanese population, consisting of 798 AIS patients and 637 sex-matched controls. We found no association of either SNP with AIS predisposition or curve severity in the Japanese population. Considering the statistical power of the present study and the limitations of the previous reports, we conclude that the associations of rs9340799 and rs1256120 with AIS predisposition and curve severity are negative.

Association of Dental Fluorosis with Polymorphisms of Estrogen Receptor Gene in Chinese Children

Dental fluorosis (DF) is one of the important performances of endemic fluorosis. Some studies indicated that estrogen receptor (ESR) gene polymorphisms were associated with bone metabolism-related diseases. Therefore, it is possible that the variation in ESR genotypes will be associated with DF status. A case-control study was conducted among children aged 8-12 years with (n = 75) or without (n = 165) DF in China to investigate the relationship between ESR gene polymorphisms and DF. Gene polymorphisms were genotyped using the PCR-RFLP procedure. Children carrying R allele of ER RsaI had significantly increased risk of DF (Odds ratio (OR) = 1.821; 95% confidence interval (CI), 1.013-3.274) compared to children carrying r allele of ER RsaI in endemic fluorosis villages. For children with high-loaded fluoride status, carrying X allele of ESRα XbaI had a significantly decreased risk of DF (OR = 0.542; 95% CI, 0.314-0.936) compared to carrying x allele. This study provides the first evidence of an association between polymorphisms in the ESR gene with DF in high-fluoride-exposed populations. Further studies are needed to confirm the association.

Evaluation of the effects of vitamin D receptor and estrogen receptor 1 gene polymorphisms on bone mineral density in postmenopausal women

The aim of this study is to evaluate the effects of estrogen receptor 1 (ESR1) and vitamin D receptor (VDR) gene polymorphisms on bone mineral density (BMD) in a group of previously untreated osteoporotic women. Effects of demographic, environmental, and hormonal factors were also evaluated in this context. Fifty women who did not have a prior diagnosis or treatment of osteoporosis were compared with 50 nonosteoporotic postmenopausal women. Demographic and morphometric characteristics, medical history, dietary habits, exercise history, and sunlight exposure were recorded. The diagnosis of osteoporosis was made with regard to BMD measurements with DEXA. Blood samples were obtained for serum biochemistry, bone turnover markers, and VDR and ESR1 gene polymorphism analysis. Polymorphic sites of VDR and ESR1 genes were amplified by polymerase chain reaction and examined using restriction fragment length polymorphism. Bb genotype was significantly higher in the osteoporotic group when compared to controls (p=0.022). Each 1 U decrease in the body mass index (BMI) increased the risk of osteoporosis by 8% independent of the genotype. We could not observe a significant effect of ESR1 polymorphism on BMD or osteoporosis risk. The interaction of ApaI and BsmI genotypes were found to be significant (p=0.041) and the AaBb genotype, when corrected for BMI, was shown to increase the risk of osteoporosis five times (p=0.005). However, the results demonstrated insignificant p values when correction for multiple testing was performed with the Bonferroni method in the logistic regression model. A predominance of Bb genotype of the VDR gene was evident in this group of postmenopausal Turkish women. Moreover, the combined genotype AaBb conferred a five times increased risk for osteoporosis when corrected for clinical variables.

Association between estrogen receptor gene polymorphism and systemic lupus erythematosus in women of Han nationality from Jiangxi province.

Objective To explore the association between estrogen receptor gene polymorphism and systemic lupus erythematosns in women of Han nationality from Jiangxi province.Methods Whole blood samples were obtained from 95 female patients with SLE of Han nationality (18 with pre-menarche onset and 77 with post-menarche onset) and 100 healthy female controls from Jiangxi province.Genomic DNA was extracted from these samples followed by the analysis of polymorphism at Pvu Ⅱ and Xba I sites of estrogen receptor alpha gene with PCR-restriction fragment length polymorphism (RFLP).The frequencies of alleles and genotypes were compared between the control and patients and between patients with pre-menarche onset and those with post-menarche onset.Results The frequency of P allele was higher in patients with SLE than in the controls (35.8% vs 27%,P<0.05),but lower in patients with pre-menarche onset than in those with post-menarche onset (19.4% vs 39.6%,P<0.05).Further more,an increment was observed in the frequency of Xxpp genotype in patients with pre-menarche onset compared with normal controls and patients with postmenarche onset (16.7% vs 1% and 1.3%,both P<0.05).Conclusions The frequency of P allele in ER alpha gene is increased in female patients with SLE of Han nationality from Jiangxi province.The Xxpp genotype of ER gene may be associated with the susceptibility to pre-menarche onset SLE. Key words: Lupus erythematosus,systemic; Receptors,estrogen; Polymorphism,restriction fragment length

Polymorphisms of caffeine metabolism and estrogen receptor genes and risk of Parkinson's disease in men and women

Caffeine intake has been associated with a decreased risk of Parkinson's disease (PD) in men but the effect in women is less clear, and appears to be modified by use of post-menopausal estrogens. In a nested case–control study within the Nurses Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), we examined associations between single nucleotide polymorphisms (SNPs) of caffeine metabolizing genes (CYP1A2 and NAT2) and estrogen receptors (ESR1 and ESR2), their interaction with caffeine intake and hormone replacement therapy (PMH) use (collected prospectively) and risk of PD. We matched 159 female cases to 724 controls and 139 male cases to 561 controls on birth year, source of DNA (blood or buccal smear), age and sex. The CYP1A2 rs762551 polymorphism (lower enzyme inducibility) was marginally associated with an increased risk of PD (RR, for increasing number of minor alleles = 1.34; 95% CI 1.02, 1.78 in women, but not in men. None of the NAT2 (classified as slow vs. fast acetylator), ESR1 or ESR2 polymorphisms were significantly associated with an altered risk of PD. Marginally significant interactions were observed between caffeine intake and the ESR1 polymorphism rs3798577 ( p = 0.07) and ESR2 polymorphism rs1255998 ( p = 0.07). The observed increased risk of PD among female but not male carriers of the rs762551 polymorphism of CYP1A2 and the interactions of caffeine with ESR1 rs3798577 and ESR2 rs1255998 may provide clues to explain the relationship between gender, caffeine intake, estrogen status and risk of PD and need to be replicated.

Estrogen receptor 1, Glutathione S-transferase P1, Glutathione S-transferase M1, and Glutathione S-transferase T1 Genes with Dysmenorrhea in Korean Female Adolescents

Dysmenorrhea is the most common gynecologic complaint among adolescent females. We investigated the association between genetic polymorphisms and dysmenorrhea. A total of 202 postmenarcheal Korean female adolescents 16-17 yr old participated in this study. Genotyping for glutathione S-transferase mu 1 (GSTM1), glutathione S-transferase theta 1 (GSTT1), glutathione S-transferase pi 1 (GSTP1), and estrogen receptor 1 (ESR1) was performed using PCR-based methods. The PP+Pp genotype of the ESR1 gene was more frequent than pp genotypes in subjects with dysmenorrhea than in subjects without dysmenorrhea (odds ratio=2.440; 95% confidence interval, 1.036-5.753; P=0.040) using an unadjusted univariate logistic regression analysis. The relationship between dysmenorrhea and ESR1 gene polymorphisms remained significant after adjustment for premenstrual syndrome, years elapsed after menarche, and family history of dysmenorrhea. No significant difference was observed between subjects with dysmenorrhea and subjects without dysmenorrhea for polymorphisms of GSTM1, GSTT1, and GSTP1 genes. Our results suggest that ESR1 gene polymorphisms may be associated with dysmenorrhea.

Estrogen Receptor Signaling and Its Relationship to Cytokines in Systemic Lupus Erythematosus

Dysregulation of cytokines is among the main abnormalities in Systemic Lupus Erythematosus (SLE). However, although, estrogens, which are known to be involved in lupus disease, influence cytokine production, the underlying molecular mechanisms remain poorly defined. Recent evidence demonstrates the presence of estrogen receptor in various cell types of the immune system, while divergent effects of estrogens on the cytokine regulation are thought to be implicated. In this paper, we provide an overview of the current knowledge as to how estrogen-induced modulation of cytokine production in SLE is mediated by the estrogen receptor while simultaneously clarifying various aspects of estrogen receptor signaling in this disease. The estrogen receptor subtypes, their structure, and the mode of action of estrogens by gene activation and via extranuclear effects are briefly presented. Results regarding the possible correlation between estrogen receptor gene polymorphisms and quantitative changes in the receptor protein to SLE pathology and cytokine production are reviewed.

Association between Estrogen Receptor Gene Polymorphisms and Depression in Post-Menopausal Women: A Preliminary Study

Post-menopausal women experience variable biological and psychological changes. The effect of reduced levels of estrogen can effect on post-menopausal depression. Estrogen triggers physiological responses by binding to the estrogen receptor (ER). Two subtypes of ER, ERa and ERb are now known. We investigated the significance of ERa and ERb polymorphisms and post-menopasal depression in this study. Forty three women with post-menopausal depression and 63 post-menopausal women without depression as normal controls were recruited. Polymerase chain reaction-restriction fragment length polymorphism method was used to investigate genotypes of ERa and ERb polymorphisms. Genotypes of PvuII and XbaI polymorphism of ERa receptor were significantly different in patients with post-menopausal depression comparing with controls. Genotypes of ERb did not show association with post-menopausal depression. Our study showed that ERa receptor polymorphism had an association with depression in post-menopausal women. It suggests that investigation of ER genes and their functions might be important for understanding pathophysilogical mechanism of post-menopausal depression.

Association between estrogen receptor gene polymorphisms and breast density in postmenopausal women

Objectives The aim of this study was to evaluate the association between clinical characteristics and polymorphisms HaeIII, MspI and XbaI of the estrogen receptor gene α with postmenopausal mammographic density.Methods A prospective study was performed with 120 women who were not users of hormones and had no identified breast lesions. All of them underwent bilateral mammography; the radiological density was determined by three independent observers, with two subjective evaluations based on the ACR-BIRADS® classification of mammographic patterns, 2003, and one computerized evaluation using the gray-scale histogram tool of the Adobe Photoshop® 7.0 software. Peripheral blood samples were obtained for DNA extraction, performed according to the GFX® Kit protocol (Amersham-Pharmacia). Polymerase chain reaction restriction fragment length polymorphism was carried out for an analysis of the polymorphisms present in intron 1 (HaeIII and XbaI) and in exon 1 (MspI) of the estrogen receptor gene.Results There was a high degree of concordance among the observers in the determination of mammary density (Kappa, Pearson and Spearman, p < 0.001). The associations of clinical characteristics with mammary density were: age (p = 0.04), body mass index (p < 0.0001) and age at menarche (p = 0.02). The relationship between the allele distribution of the polymorphisms and density was: XbaI (p = 0.02), HaeIII (p = 0.65) and MspI (p = 0.65).Conclusions Our data suggested that the polymorphism XbaI may be strongly related to mammographic density.

Estrogen receptor gene polymorphisms in patients with idiopathic premature ovarian failure

It has been reported that polymorphisms in the estrogen receptor (ER)-alpha gene (ESR1) may be associated with reproductive patterns of women. This study was performed to investigate whether the genetic polymorphisms of the ER-alpha gene are associated with idiopathic premature ovarian failure (POF) in a Korean population. The subjects were 126 idiopathic POF patients and 221 post-menopausal controls recruited from university hospitals between 1999 and 2004. Genotyping was performed by MGB primer/probe Taqman assay. Haplotypes were deduced by using the Haploview version 4.1. Bonferroni correction was applied for the correction of multiple testing. There was no significant difference in the allele distribution of the ER-alpha gene (TA)n repeats between the POF and the control group. For the PvuII polymorphism, the POF group showed a higher frequency of TT genotype compared with the controls (41.3 versus 26.3%, P = 0.004, 98.75% CI 1.8-28.2%). No significant difference was found in the distribution of the XbaI polymorphism between the POF and the control group. Haplotype analysis showed that the frequency of TA haplotype was significantly higher in the POF patients compared with the controls (64.7 versus 52.7%, P = 0.002, 98.75% CI 2.4-21.6%). These findings suggest that the ER-alpha gene polymorphisms may be associated with idiopathic POF.

Possible Association of Combined Vitamin D Receptor and Estrogen Receptor Genotypes and Low Bone Mineral Density in Jordanian Postmenopausal Women

The genetics of osteoporosis has been extensively studied over the last 20 years. Many of the studies have been aimed at identifying possible risk factors and possible association with low bone mineral density (BMD). Vitamin D receptor (VDR) and estrogen receptor (ER) gene polymorphisms were the first to be studied. Some studies have shown a possible association for individual VDR and ER or combined VDR and ER genotypes in some populations, and others showed lack of such an association. This study is aiming at identification of a possible association with low BMD in Jordanian postmenopausal women. We used restriction fragment length polymorphisms (RFLPs) to study four polymorphisms in the VDR gene and two polymorphisms in the ER gene. Our sample was composed of 100 normal controls and 120 samples from patients with symptomatic vertebral fractures. The results showed a possible association of the ppxx genotype with low BMD in controls and patients and an association of the AaBbTT genotype with high BMD in control subjects. The AABBTT, AABBTTFF, and AABBTTFFPPXX genotypes showed a possible association with low BMD in patients. Further studies are needed to confirm the last finding since it could be an important predictor of low BMD in the Jordanian population.

Association of testicular germ cell tumor with polymorphisms in estrogen receptor and steroid metabolism genes

It is generally assumed that the development of testicular germ cell tumor (TGCT) is under endocrine control. In particular, unbalanced androgen/estrogen levels and/or activity are believed to represent the key events for TGCT development and progression. Furthermore, recent evidence has suggested a strong genetic component for TGCT. In this study, we analyzed whether a genetic variation in estrogen receptor (ESR) genes and steroid hormone metabolism genes is associated with TGCT. We genotyped for 17 polymorphic markers in 11 genes in 234 TGCT cases and 218 controls: ESR (ESR1 and ESR2); CYP19A1 (aromatase); 17beta-hydroxysteroid dehydrogenase types 1 and 4 (HSD17B1 and HSD17B4) dehydrogenases that convert potent androgens and estrogens to weak hormones; cytochrome P450 hydroxylating enzymes CYP1A1, CYP1A2, and CYP1B1; and the metabolic enzymes COMT, SULT1A1, and SULT1E1. We observed a significant association of rs11205 in HSD17B4 with TGCT. TGCT risk was increased twofold per copy of the minor A allele at this locus (odds ratios (OR)=2.273, 95% confidence interval (CI)=1.737-2.973). Homozygous carriage of the minor A allele was associated with an over fourfold increased risk of TGCT (OR=4.561, 95% CI=2.615-7.955) compared with homozygous carriage of the major G allele. The risk was increased both for seminoma (OR=5.327, 95% CI=2.857-9.931) and for nonseminoma (OR=3.222, 95% CI=1.471-7.059). We found for the first time an association of polymorphisms in HSD17B4 gene with TGCT. Our findings expand the current knowledge on the role of genetic contribution in testicular cancer susceptibility, and support the hypothesis that variations in hormone metabolism genes might change the hormonal environment implicated in testicular carcinogenesis.

Association between adolescent idiopathic scoliosis with double curve and polymorphisms of calmodulin1 gene/estrogen receptor‐α gene

To investigate whether single nucleotide polymorphisms (SNP) of the calmodulin1 (CALM1) and estrogen receptor-α genes correlate with double curve in adolescent idiopathic scoliosis (AIS). A total of 67 Chinese patients with AIS with double curve and 100 healthy controls were recruited. Curve pattern and Cobb angle of each patient were recorded. The Cobb angle is at least 30°. There were 60 patients with Cobb angle ≥ 40°. According to the apical location of the major curve, there were 40 thoracic curve patients. Four polymorphic loci, including rs12885713 (-16C > T) and rs5871 in the CALM1 gene and rs2234693 (Pvu II) and rs9340799 (Xba I) in the estrogen receptor 1 (ER1) gene were analyzed by the ABI3730 genetic analyzer. The current study indicates that: (i) there are statistical differences between patients with double curve, with Cobb angle ≥ 40° and with thoracic curve and healthy controls in the polymorphic distribution of the rs2234693 site of the ER1 gene, (P= 0.014, 0.0128, 0.0184 respectively); (ii) there is a difference between patients with double curve and controls in the polymorphic distribution of the rs12885713 site in the CALM1 gene (P= 0.034); and (iii) there is a difference between thoracic curve patients and controls in the polymorphic distribution of the rs5871 site in the CALM1 gene (P= 0.0102). Different subtypes of AIS might be related to different SNP. A combination of CALM1 and ER1 gene polymorphisms might be related to double curve in patients with AIS. Further study is necessary to confirm these hypotheses.

Relationship between single nucleotide polymorphism of estrogen receptor gene and endocrine therapy efficacy in breast cancer

1113 Objective: To explore the distribution of single nucleotide polymorphism (SNP) loci of estrogen receptor (ESR1) gene in breast cancer patients and to study the relationship between the SNP genotypes and the efficacy to endocrine therapy. Methods: Fifteen SNP loci ( rs872921 , rs2077647, rs3904766, rs2234693, rs11155816, rs827419 , rs2347867, rs3798759, rs1801132, rs985191 , rs9340931, rs9397463, rs722209 , rs3778099, and rs3798577) of ESR1 gene were selected as genetic markers. PCR-restriction fragment length polymorphisms, PCR-DNA sequencing and allele-specific real time PCR methods were employed to analyze the loci genotype of 240 patients with breast cancer accepted endocrine therapy. Results: The loci rs872921 and rs3904766 were abandoned for poor ploymorphisms, and the other 13 loci had polymorphisms. The frequencies of alleles and genotypes of rs2077647 and rs3798759 were significantly related with the efficacy of endocrine therapy (p &lt; 0. 05). The linkage disequilibrium and the hapotype analysis showed that there were four linkage disequilibrium blocks in ESR1 gene. They were rs2077647∼rs2234693 (LD1), rs2234693∼rs11155816 (LD2), rs9397463∼ rs722209 (LD3), and rs3778099∼rs3798577 (LD4), and the hapotypes of LD2, LD3, s11155816- rs827419 , and rs2347867- rs1801132 were positively related with the efficacy of endocrine therapy (p &lt; 0. 05). Conclusions: Some of the polymorphisms of ESR1 gene and the haplotypes are positively associated with the endocrine therapy efficacy, and maybe account for predicting the endocrine response in breast cancer. No significant financial relationships to disclose.

Isoflavone, polymorphisms in estrogen receptor genes and breast cancer risk in case‐control studies in Japanese, Japanese Brazilians and non‐Japanese Brazilians

Epidemiologic studies have shown an inverse association between isoflavones and breast cancer risk. Because isoflavones bind estrogen receptors, we hypothesized that polymorphisms in the estrogen receptor genes might modify the association between isoflavone intake and breast cancer risk. We conducted hospital-based case-control studies of patients aged 20-74 years with primary, incident, histologically confirmed invasive breast cancer, and matched controls from among medical checkup examinees in Nagano, Japan, and from cancer-free patients in São Paulo, Brazil. A total of 846 pairs (388 Japanese, 79 Japanese Brazilians and 379 non-Japanese Brazilians) completed validated food frequency questionnaires, and provided blood samples. Five single nucleotide polymorphisms in the estrogen receptor alpha (rs9340799, rs1913474, and rs2234693) and beta (rs4986938 and rs1256049) genes were genotyped. We found no consistent association between the five single nucleotide polymorphisms and breast cancer risk among the three populations. In analyses of combinations of isoflavone intake and single nucleotide polymorphisms, an inverse association between intake and risk was limited to women with the GG genotype of the rs4986938 polymorphism for postmenopausal Japanese (odds ratio for highest versus lowest tertile = 0.47; P for trend = 0.01), Japanese Brazilians (odds ratio for highest versus lowest median = 0.31) and non-Japanese Brazilians (odds ratio for consumers versus non-consumers = 0.37) (P for interaction = 0.11, 0.08, and 0.21, respectively). We found no remarkable difference for the other four polymorphisms. Our findings suggest that polymorphisms in the estrogen receptor beta gene may modify the association between isoflavone intake and breast cancer risk.

Association between estrogen receptor gene polymorphisms and breast density in postmenopausal women

Association between estrogen receptor gene polymorphisms and breast density in postmenopausal women

Does estrogen receptor gene polymorphism play a role in Parkinson's disease?

This study was designed to investigate the frequency of estrogen receptor (ER) gene polymorphism in Chinese patients with Parkinson's disease (PD). Polymerase chain reaction (PCR) method and restriction fragment length polymorphism (RFLP) were used to detect the ER gene polymorphisms in 158 PD patients and 146 healthy controls. In the PD and control groups, “x” accounted for 83.5% and 80.8%, respectively ( P > 0.05). “xx” was found in 77.2% of the PD group and in 69.9% of the control group ( P > 0.05). The frequency of “p” in the PD and control group was 67.7% and 64.0%, respectively ( P > 0.05). “pp” was 51.9% in the PD group and 43.8% in the control group ( P > 0.05). “ppxx” was found in 49.4% of the PD and 43.0% of the control subjects ( P > 0.05). There was no significant difference in the “x”, “xx”, “p”, “pp” or “ppxx” between males and females within the PD or control groups. In conclusion, we found no significant differences in the genotype or allele frequencies between patients with Parkinson's disease and healthy subjects. These findings suggest that the estrogen receptor gene polymorphism may not play a key role in the pathogenesis PD in Chinese patients.

Viral Vector–mediated Delivery of Estrogen Receptor-α to the Hippocampus Improves Spatial Learning in Estrogen Receptor-α Knockout Mice

Estrogen, which influences both classical genomic and rapid membrane-associated signaling cascades, has been implicated in the regulation of hippocampal function, including spatial learning. Gene mutation studies suggest that estrogen effects are mediated by estrogen receptor-α (ER-α); however, because gonadal steroids influence the organization of the hippocampus during development, it has been difficult to distinguish developmental effects from those specific to adults. In this study we show that lentiviral delivery of the gene encoding ER-α to the hippocampus of adult ER-α-knockout (ER-αKO) mice restores hippocampal responsiveness to estrogen and rescues spatial learning. We propose that constitutive estrogen receptor activity is important for maintaining hippocampus-dependent memory function in adults.