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Liu F, Day M, Muñiz LC, Bitran D, Arias R, Revilla-Sanchez R, Grauer S, Zhang G, Kelley C, Pulito V, Sung A, Mervis RF, Navarra R, Hirst WD, Reinhart PH, Marquis KL, Moss SJ, Pangalos MN, Brandon NJ. Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory. Nat Neurosci. 2008 Mar;11(3):334-43. PubMed.
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University of California, Los Angeles
This study investigated cellular and molecular mechanisms that underlie changes in estrogen-mediated effects on synaptic plasticity and hippocampal-dependent spatial memory. The particular focus is on whether Wyeth compounds, specifically estrogen receptor β (ERβ) agonists, can mediate these beneficial effects of estrogen treatment. Much data are shown that are consistent with a beneficial action of their ERβ agonist on these cellular and molecular mechanisms, as well as on behavioral tests of memory.
It is somewhat problematic, however, that the authors switch back and forth between rats and mice when addressing the different mechanisms. It is known that ERα and ERβ expression in the brain differ between mice and rats. Thus, for consistency, it would have been desirable to have all mechanisms studied in their entirety in at least one species. Notably, extrapolation of findings to humans should be made with caution for the same reason.
In addition, some experiments were done in females and others in males. Further, some had undergone gonadectomy and others were gonadally intact. Since sex hormones can affect ER expression, different results may occur in each of these scenarios. Indeed, there are inconsistencies in the results in the paper between these variables that are not addressed.
Finally, it has previously been shown that states of disease, such as stroke, can alter ER expression in the brain. This study was done in normal, healthy rodents. Therefore, one cannot assume that observing ERβ-mediated beneficial effects on a variety of mechanisms during health will also be the case in states of diseases like Alzheimer’s.
Karolinska institute
There is evidence that estradiol (E2) modulates many advanced brain functions, including hippocampus-dependent learning and memory. Several independent studies have demonstrated beneficial effects of estrogen replacement on cognition in normally aging women and in women suffering from dementia associated with Alzheimer disease. Estrogen affects brain function through estrogen receptors (ERα and ERβ), which have been found in the hippocampus and cortex. We have demonstrated that ERβ is the predominant estrogen receptor expressed in the hippocampus and cortex during embryogenesis; loss of ERβ causes brain malformation (Fan et al., 2006; Wang et al., 2003). All of these data indicate that estrogen can affect hippocampus function, but the underlying mechanism is not clear.
Liu et al. in this paper have explored estrogen effects on hippocampal synaptic plasticity and memory through estrogen receptor β. An in vivo study showed that key synaptic proteins including PSD-95, synaptophysin, and the AMPA-receptor subunit GluR1 were increased by selective ERβ agonists. In hippocampal slices, ERβ activation enhanced long-term potentiation. All of these effects were absent in ERβ knockout mice. This is the first demonstration of ERβ receptor activation of hippocampal plasticity.
Another study previously found that estradiol stimulates glutamatergic synapse formation in the developing hippocampus through an ERα-dependent mechanism (Jelks et al., 2007). It is likely that ERα and ERβ act on separate pathways with different mechanisms in the hippocampus. Several studies have reported that loss of ERβ induces dysfunction of hippocampus-dependent learning and memory (Rissman et al., 2002; Day et al., 2005).
The present study demonstrates that an ERβ agonist can improve performance in hippocampus-dependent memory tasks. All of these data support a role of ERβ for hippocampus-dependent cognition. Another study showed that estradiol via estrogen receptor β improves cerebellar memory formation (Andreescu et al., 2007).
Alzheimer disease (AD) is the primary cause of dementia and memory loss in the elderly, and is characterized by an insidious development of hippocampal pathology. The present study shows that activation of ERβ may offer a new therapeutic approach for diseases with cognitive deficits such as Alzheimer’s and schizophrenia. Clinical trials have shown that estrogen cannot slow the progression of already diagnosed AD, and estrogen replacement can prevent rather than reverse neurodegeneration. More research is needed to find out the function of estrogen in the brain under normal and pathological conditions, and to determine if estrogen may play some role in AD. Since this study clearly has demonstrated that estrogen affects hippocampus-dependent cognition through estrogen receptor β, ERβ agonists may be a better choice than estrogen for improving cognition.
References:
Fan X, Warner M, Gustafsson JA. Estrogen receptor beta expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons. Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19338-43. Epub 2006 Dec 11 PubMed.
Wang L, Andersson S, Warner M, Gustafsson JA. Estrogen receptor (ER)beta knockout mice reveal a role for ERbeta in migration of cortical neurons in the developing brain. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):703-8. PubMed.
Jelks KB, Wylie R, Floyd CL, McAllister AK, Wise P. Estradiol targets synaptic proteins to induce glutamatergic synapse formation in cultured hippocampal neurons: critical role of estrogen receptor-alpha. J Neurosci. 2007 Jun 27;27(26):6903-13. PubMed.
Rissman EF, Heck AL, Leonard JE, Shupnik MA, Gustafsson JA. Disruption of estrogen receptor beta gene impairs spatial learning in female mice. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3996-4001. PubMed.
Day M, Sung A, Logue S, Bowlby M, Arias R. Beta estrogen receptor knockout (BERKO) mice present attenuated hippocampal CA1 long-term potentiation and related memory deficits in contextual fear conditioning. Behav Brain Res. 2005 Oct 14;164(1):128-31. PubMed.
Andreescu CE, Milojkovic BA, Haasdijk ED, Kramer P, de Jong FH, Krust A, De Zeeuw CI, De Jeu MT. Estradiol improves cerebellar memory formation by activating estrogen receptor beta. J Neurosci. 2007 Oct 3;27(40):10832-9. PubMed.
University of Illinois at Urbana-Champaign
In this manuscript, Liu et al. convincingly demonstrate that activation of ERβ positively regulates synaptic plasticity and enhances long-term potentiation in the adult rodent hippocampus, providing the basis for structural and physiological changes underlying learning and memory. Consistently, the authors demonstrate that the ERβ agonist WAY-200070 improves hippocampus-dependent spatial memory. Thus, this study elucidates a novel ERβ-dependent mechanism by which estrogen enhances hippocampal synaptic plasticity and improves memory, and supports a study demonstrating that ERβ is a prerequisite for optimal spatial learning in mice (Rissman et al., 2002). In addition, the present study reveals that WAY-200070 increases phospho-CREB via a rapid, “non-genomic” mechanism. Milner et al. (2005) has recently demonstrated that ERβ is extensively expressed at extranuclear locations within the hippocampal neurons, suggesting that ERβ may serve primarily as a non-genomic transducer of estrogen actions in the hippocampus. In humans, ERβ seems to the predominant ER subtype found in the adult hippocampus (González et al., 2007).
Recently, our laboratory has demonstrated that activation of ERα induces glutamatergic synapse formation in the developing hippocampus within a time frame during which hippocampal ERα expression is transiently increased in neonates. Furthermore, we have previously demonstrated that ERα, but not ERβ, mediates the ability of estrogen to protect the brain against ischemic injury (Dubal et al., 2001). Consistently, ischemic stroke injury upregulates the expression of ERα in the injured brain (Dubal et al., 1999). We hypothesize that the dramatic re-expression of ERα following injury is a recapitulation of its expression during development when E2 plays pivotal trophic roles in the brain. Together, these findings indicate that the hippocampus is capable of responding to both ERα and ERβ to potentially improve cognitive functions, depending on the ER subtypes that are available in specific physiological as well as neurodegenerative conditions.
Recent results from the Woman’s Health Initiative Memory Study (WHIMS) have been reported that hormone therapy (HT) improves cognitive performance when given within five years after the onset of menopause, but not after a prolonged period of hypoestrogenicity. The duration from loss of ovarian hormone production to the initiation of HT also seems to dictate the beneficial actions of estrogen in stroke injury. Despite numerous observational and retrospective studies demonstrating cerebrovascular benefits of HT among postmenopausal women, the WHI reported that HT increased the risk for stroke, or afforded no benefit. The vast majority of women in the WHI were on average 12 years postmenopausal prior to the initiation of HT, whereas in observational studies that reported beneficial effects of HT, the majority of subjects initiated hormone replacement in their perimenopausal period. We have recently demonstrated that a long duration from surgically induced menopause to the initiation of estrogen reintroduction disrupts the beneficial effects of estrogen on the outcomes of experimentally induced ischemic stroke, as well as the ability of the injured brain to upregulate ERα expression (Suzuki et al., 2007). It is intriguing to speculate that a prolonged period of hypoestrogenicity may also disrupt ER expression in the hippocampus, causing diminished responsiveness of the hippocampal neurons to HT to produce positive effects on cognitive function. A therapeutic approach to maintain or to enhance the expression of specific ER subtypes, in addition to HT in the form of 17β-estradiol, ERα or ERβ agonists, may prove to confer beneficial actions against a variety of neurodegenerative conditions including cerebrovascular stroke and Alzheimer disease.
References:
Rissman EF, Heck AL, Leonard JE, Shupnik MA, Gustafsson JA. Disruption of estrogen receptor beta gene impairs spatial learning in female mice. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3996-4001. PubMed.
Milner TA, Ayoola K, Drake CT, Herrick SP, Tabori NE, McEwen BS, Warrier S, Alves SE. Ultrastructural localization of estrogen receptor beta immunoreactivity in the rat hippocampal formation. J Comp Neurol. 2005 Oct 17;491(2):81-95. PubMed.
González M, Cabrera-Socorro A, Pérez-García CG, Fraser JD, López FJ, Alonso R, Meyer G. Distribution patterns of estrogen receptor alpha and beta in the human cortex and hippocampus during development and adulthood. J Comp Neurol. 2007 Aug 20;503(6):790-802. PubMed.
Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, Kindy MS, Wise PM. Estrogen receptor alpha, not beta, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1952-7. PubMed.
Dubal DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM. Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. J Neurosci. 1999 Aug 1;19(15):6385-93. PubMed.
Suzuki S, Brown CM, Dela Cruz CD, Yang E, Bridwell DA, Wise PM. Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):6013-8. PubMed.
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