Role of Estrogen Receptor α and β in Preserving Hippocampal Function during Aging

Han, Xiao-Xia; Aenlle, Kristina K.; Bean, Linda A.; Rani, Asha; Semple‐Rowland, Susan L.; Kumar, Ashok; Foster, Thomas C.

doi:10.1523/jneurosci.4937-12.2013

Cited by 80 publications

(82 citation statements)

References 92 publications

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“…These results provide support for a differential role of ER␣ and ER␤ in hippocampal function (Foster, 2012a;Han et al, 2013;Bean et al, 2014). Studies using ER␣ knock-out (ER␣KO) mice demonstrate that ER␣ is important for maintaining memory in adults Fugger et al, 2000;Han et al, 2013). Similar to the current study, viral expression of hippocampal ER␤ in ER␤KO mice impairs spatial learning (Han et al, 2013).…”

Section: Discussionsupporting

confidence: 82%

“…3C,D) confirmed protein expression in the dorsal hippocampus 4 weeks after injection. Similar to our previous results, expression was largely limited to region CA1 of the hippocampus Han et al, 2013). Together, these results established the efficacy of our expression vectors.…”

Section: Functional Characterization Of Er-containing Plasmids and Virussupporting

confidence: 91%

“…Studies using ER␣ knock-out (ER␣KO) mice demonstrate that ER␣ is important for maintaining memory in adults Fugger et al, 2000;Han et al, 2013). Similar to the current study, viral expression of hippocampal ER␤ in ER␤KO mice impairs spatial learning (Han et al, 2013). The impairment may result from ER␤ inhibition of ER␣-mediated transcription rendering the hippocampus more vulnerable to the stressors of aging (Foster, , 2012aBean et al, 2014).…”

Section: Discussionsupporting

confidence: 68%

“…For ER␤-transfected cells, SEAP expression was not altered in the absence of EB treatment and expression increased dose dependently after EB treatment. These results indicate that the receptors are functional and confirm that ER␣ is more effective than ER␤ in inducing transcription (Foster, 2012a;Han et al, 2013).…”

Section: Functional Characterization Of Er-containing Plasmids and Virusmentioning

confidence: 63%

“…Expression of both ER subtypes declines in the hippocampus of aged rodent models (Adams et al, 2002;Mehra et al, 2005;Waters et al, 2011;. Studies using viral-vector-mediated expression of hippocampal ER␣ and ER␤ suggest that ER␣ is critical in maintaining cognitive function in young and middle-aged animals Witty et al, 2012;Han et al, 2013). These results suggest that closing of the therapeutic window may be due to decreased activity of ER␣ and/or ER␤ and that increased receptor expression in the hippocampus could rejuvenate estrogen responsiveness and reopen the therapeutic window.…”

Section: Introductionmentioning

confidence: 99%

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Re-Opening the Critical Window for Estrogen Therapy

et al. 2015

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A decline in estradiol (E2)-mediated cognitive benefits denotes a critical window for the therapeutic effects of E2, but the mechanism for closing of the critical window is unknown. We hypothesized that upregulating the expression of estrogen receptor ␣ (ER␣) or estrogen receptor ␤ (ER␤) in the hippocampus of aged animals would restore the therapeutic potential of E2 treatments and rejuvenate E2-induced hippocampal plasticity. Female rats (15 months) were ovariectomized, and, 14 weeks later, adeno-associated viral vectors were used to express ER␣, ER␤, or green fluorescent protein (GFP) in the CA1 region of the dorsal hippocampus. Animals were subsequently treated for 5 weeks with cyclic injections of 17␤-estradiol-3-benzoate (EB, 10 g) or oil vehicle. Spatial memory was examined 48 h after EB/oil treatment. EB treatment in the GFP (GFP ϩ EB) and ER␤ (ER␤ ϩ EB) groups failed to improve episodic spatial memory relative to oil-treated animals, indicating closing of the critical window. Expression of ER␤ failed to improve cognition and was associated with a modest learning impairment. Cognitive benefits were specific to animals expressing ER␣ that received EB treatment (ER␣ ϩ EB), such that memory was improved relative to ER␣ ϩ oil and GFP ϩ EB. Similarly, ER␣ ϩ EB animals exhibited enhanced NMDAR-mediated synaptic transmission compared with the ER␣ ϩ oil and GFP ϩ EB groups. This is the first demonstration that the window for E2-mediated benefits on cognition and hippocampal E2 responsiveness can be reinstated by increased expression of ER␣.

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Section: Discussionsupporting

confidence: 82%

Section: Functional Characterization Of Er-containing Plasmids and Virussupporting

confidence: 91%

Section: Discussionsupporting

confidence: 68%

Section: Functional Characterization Of Er-containing Plasmids and Virusmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

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Re-Opening the Critical Window for Estrogen Therapy

et al. 2015

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The stability of the transcriptome during the estrous cycle in four regions of the mouse brain

DiCarlo

Vied

Nowakowski

2017

J of Comparative Neurology

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We analyzed the transcriptome of the C57BL/6J mouse hypothalamus, hippocampus, neocortex, and cerebellum to determine estrous cycle-specific changes in these four brain regions. We found almost 16,000 genes are present in one or more of the brain areas but only 210 genes, ∼1.3%, are significantly changed as a result of the estrous cycle. The hippocampus has the largest number of differentially expressed genes (DEGs) (82), followed by the neocortex (76), hypothalamus (63), and cerebellum (26). Most of these DEGs (186/210) are differentially expressed in only one of the four brain regions. A key finding is the unique expression pattern of growth hormone (Gh) and prolactin (Prl). Gh and Prl are the only DEGs to be expressed during only one stage of the estrous cycle (metestrus). To gain insight into the function of the DEGs, we examined gene ontology and phenotype enrichment and found significant enrichment for genes associated with myelination, hormone stimulus, and abnormal hormone levels. Additionally, 61 of the 210 DEGs are known to change in response to estrogen in the brain. 50 of the 210 genes differentially expressed as a result of the estrous cycle are related to myelin and oligodendrocytes and 12 of the 63 DEGs in the hypothalamus are oligodendrocyte- and myelin-specific genes. This transcriptomic analysis reveals that gene expression in the female mouse brain is remarkably stable during the estrous cycle and demonstrates that the genes that do fluctuate are functionally related.

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Contribution of estrogen receptor subtypes, ERα, ERβ, and GPER1 in rapid estradiol-mediated enhancement of hippocampal synaptic transmission in mice

et al. 2015

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Estradiol rapidly modulates hippocampal synaptic plasticity and synaptic transmission; however, the contribution of the various estrogen receptors to rapid changes in synaptic function is unclear. The current study examined the effect of estrogen receptor selective agonists on hippocampal synaptic transmission in slices obtained from 3-5 month old wild type (WT), estrogen receptor alpha (ERαKO), and beta (ERβKO) knockout female ovariectomized mice. Hippocampal slices were prepared 10-16 days following ovariectomy and extracellular excitatory postsynaptic field potentials were recorded from CA3-CA1 synaptic contacts before and following application of 17β-estradiol-3-benzoate (EB, 100 pM), the G-protein estrogen receptor 1 (GPER1) agonist G1 (100 nM), the ERα selective agonist propyl pyrazole triol (PPT, 100 nM), or the ERβ selective agonist diarylpropionitrile (DPN, 1 μM). Across all groups, EB and G1 increased the synaptic response to a similar extent. Furthermore, prior G1 application occluded the EB mediated enhancement of the synaptic response and the GPER1 antagonist, G15 (100 nM), inhibited the enhancement of the synaptic response induced by EB application. We confirmed that the ERα and ERβ selective agonists (PPT, DPN) had effects on synaptic responses specific to animals that expressed the relevant receptor; however, PPT and DPN produced only a small increase in synaptic transmission relative to EB or the GPER1 agonist. We demonstrate that the increase in synaptic transmission is blocked by inhibition of extracellular signal-regulated kinase (ERK) activity. Furthermore, EB was able to increase ERK activity regardless of genotype. These results suggest that ERK activation and enhancement of synaptic transmission by EB involves multiple estrogen receptor subtypes.

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Role of Estrogen Receptor α and β in Preserving Hippocampal Function during Aging

Cited by 80 publications

References 92 publications

Re-Opening the Critical Window for Estrogen Therapy

Re-Opening the Critical Window for Estrogen Therapy

The stability of the transcriptome during the estrous cycle in four regions of the mouse brain

Contribution of estrogen receptor subtypes, ERα, ERβ, and GPER1 in rapid estradiol-mediated enhancement of hippocampal synaptic transmission in mice

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