Contribution of estrogen receptors alpha and beta to the effects of estradiol in the brain. J Steroid Biochem Mol Biol
Molecular Endocrinology and Oncology Research Center, Medical Center and Faculty of Pharmacy, Laval University, 2705 Laurier Boulevard, Sainte-Foy, Québec, Canada. The Journal of Steroid Biochemistry and Molecular Biology
(Impact Factor: 3.63).
03/2008; 108(3-5):327-38. DOI: 10.1016/j.jsbmb.2007.09.011
Clinical and experimental studies show a modulatory role of estrogens in the brain and suggest their beneficial action in mental and neurodegenerative diseases. The estrogen receptors ERalpha and ERbeta are present in the brain and their targeting could bring selectivity and reduced risk of cancer. Implication of ERs in the effect of estradiol on dopamine, opiate and glutamate neurotransmission is reviewed. The ERalpha agonist, PPT, is shown as estradiol to modulate hippocampal NMDA receptors and AMPA receptors in cortex and striatum of ovariectomized rats whereas the ERbeta agonist DPN is inactive. Striatal DPN activity suggests implication of ERbeta in estradiol modulation of D2 receptors and transporters in ovariectomized rats and is supported by the lack of effect of estradiol in ERbeta knockout (ERKObeta) mice. Both ERalpha and ERbeta agonists modulate striatal preproenkephalin (PPE) gene expression in ovariectomized rats. In male mice PPT protects against MPTP toxicity to striatal dopamine; this implicates Akt/GSK3beta signaling and the apoptotic regulators Bcl2 and Bad. This suggests a role for ERalpha in striatal dopamine neuroprotection. ERKOalpha mice are more susceptible to MPTP toxicity and not protected by estradiol; differences in ERKObeta mice are subtler. These results suggest therapeutic potential for the brain of ER specific agonists.
Available from: PubMed Central
- "Growing evidence suggest that the sex steroids 17β-estradiol (E2), testosterone (T) and 5α-dihydrotestosterone (DHT) may participate in rapidly modulating the long-term synaptic effects in different areas of the brain (McEwen, 2002; Isgor and Sengelaub, 2003; MacLusky et al., 2006; Hajszan et al., 2008) interacting with membrane receptors for E2 (ERs) and androgens (ARs; Kerr et al., 1995; Milner et al., 2001, 2005; Kalita et al., 2005; Tabori et al., 2005; Pedram et al., 2006; Foradori et al., 2008; Morissette et al., 2008; Raz et al., 2008; Levin, 2009). In particular, it has been shown that E2 can increase the NMDARmediated glutamatergic transmission, decrease the GABAergic one and enhance the magnitude of LTP at hippocampal CA3- CA1 glutamatergic synapses (Wong and Moss, 1992; Woolley et al., 1997; Murphy et al., 1998; Foy et al., 1999; Foy, 2001; Rudick and Wooley, 2001; Smith and McMahon, 2005, 2006; Smith et al., 2009; Hasegawa et al., 2015), while T and DHT show an opposite effect (Harley et al., 2000; Hebbard et al., 2003; Skucas et al., 2013; Hasegawa et al., 2015). "
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ABSTRACT: Estrogenic and androgenic steroids synthesized in the brain may rapidly modulate synaptic plasticity interacting with specific membrane receptors. We explored by electrophysiological recordings in hippocampal slices of male rat the influence of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) neo-synthesis on the synaptic changes induced in the CA1 region. Induction of long-term depression (LTD) and depotentiation (DP) by low frequency stimulation (LFS, 15 min-1 Hz) and of long-term potentiation (LTP) by high frequency stimulation (HFS, 1 s-100 Hz), medium (MFS, 1 s-50 Hz), or weak (WFS, 1 s-25 Hz) frequency stimulation was assayed under inhibitors of enzymes converting testosterone (T) into DHT (5α-reductase) and T into E2 (P450-aromatase). We found that LFS-LTD depends on DHT synthesis, since it was fully prevented under finasteride, an inhibitor of DHT synthesis, and rescued by exogenous DHT, while the E2 synthesis was not involved. Conversely, the full development of HFS-LTP requires the synthesis of E2, as demonstrated by the LTP reduction observed under letrozole, an inhibitor of E2 synthesis, and its full rescue by exogenous E2. For intermediate stimulation protocols DHT, but not E2 synthesis, was involved in the production of a small LTP induced by WFS, while the E2 synthesis was required for the MFS-dependent LTP. Under the combined block of DHT and E2 synthesis all stimulation frequencies induced partial LTP. Overall, these results indicate that DHT is required for converting the partial LTP into LTD whereas E2 is needed for the full expression of LTP, evidencing a key role of the neo-synthesis of sex neurosteroids in determining the direction of synaptic long-term effects.
Available from: Ana Quiroga-Varela
- "Estrogens, in particular 17β-estradiol (E2), play a fundamental role in regulating brain activity modulating neuronal expression of enzymes, receptors, structural proteins and synaptic plasticity and notably influencing cognition and behavior (Wong and Moss, 1992; Murphy and Segal, 1996; McEwen, 2002; Kramár et al., 2013). The E2 effects depend on genomic responses via nuclear receptors (Paech et al., 1997) and rapid non-genomic responses involving membrane receptors (ERα/β and GPER-1) (Kelly et al., 1976, 2002; Wong and Moss, 1992; Kelly and Levin, 2001; Qiu et al., 2003; Toran-Allerand, 2004; Revankar et al., 2005; Pedram et al., 2006; Morissette et al., 2008; Raz et al., 2008; Boulware and Mermelstein, 2009; Almey et al., 2012). The ERs may be also activated by extracellular "
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ABSTRACT: 17β-estradiol (E2), a neurosteroid synthesized by P450-aromatase (ARO), modulates various brain functions. We characterized the role of the locally synthesized E2 on striatal long-term synaptic plasticity and explored possible interactions between E2 receptors (ERs) and dopamine (DA) receptors in the dorsal striatum of adult male rats. Inhibition of E2 synthesis or antagonism of ERs prevented the induction of long-term potentiation (LTP) in both medium spiny neurons (MSNs) and cholinergic interneurons (ChIs). Activation of a D1-like DA receptor/cAMP/PKA-dependent pathway restored LTP. In MSNs exogenous E2 reversed the effect of ARO inhibition. Also antagonism of M1 muscarinic receptors prevented the D1-like receptor-mediated restoration of LTP confirming a role for ChIs in controlling the E2-mediated LTP of MSNs. A novel striatal interaction, occurring between ERs and D1-like receptors in both MSNs and ChIs, might be critical to regulate basal ganglia physiology and to compensate synaptic alterations in Parkinson’s disease.
Available from: Xiaoniu Dai
- "Numerous studies have shown that E2 exerts powerful neuroprotective actions on multiple brain regions, including the cerebral cortex, hippocampus, striatum, basal forebrain, and cerebellum (Brown et al., 2009). E2 has also demonstrated a variety of actions on the brain by regulating spine density (Gould et al., 1990), synaptic number, and synthesis of neurotrophic factors (Sohrabji et al., 1995; Smith and McMahon, 2006; Morissette et al., 2008). In addition to its well-documented neuroregulatory effects, clinical investigations have provided the evidences that postmenopausal women are more vulnerable than young women to neurodegenerative diseases such as Alzheimer's (Boada et al., 2012; Mateos et al., 2012) and Parkinson's (Al Sweidi et al., 2012; Bourque et al., 2012) diseases, cerebral ischemic injury such as stroke, and memory or cognitive dysfunctions . "
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ABSTRACT: Abstract 17β-Estradiol (E2), one of female sex hormones, has well-documented neuroprotective effects in a variety of clinical and experimental disorders of the central cerebral ischemia, including stroke and neurodegenerative diseases. The cellular mechanisms that underlie these protective effects of E2 are uncertain because a number of different cell types express estrogen receptors in the central nervous system. Astrocytes are the most abundant cells in the central nervous system and provide structural and nutritive support of neurons. They interact with neurons by cross-talk, both physiologically and pathologically. Proper astrocyte function is particularly important for neuronal survival under ischemic conditions. Dysfunction of astrocytes resulting from ischemia significantly influences the responses of other brain cells to injury. Recent studies demonstrate that estrogen receptors are expressed in astrocytes, indicating that E2 may exert multiple regulatory actions on astrocytes. Cerebral ischemia induced changes in the expression of estrogen receptors in astrocytes. In the present review, we summarize the data in support of possible roles for astrocytes in the mediation of neuroprotection by E2 against cerebral ischemia.
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