雌激素和Glu-NMDA受体通路与学习记忆相关性的研究进展

摘要/Abstract

摘要： 雌激素（Estrogen, E）是维持女性第二性征最主要的甾体物质，其在神经系统也发挥广泛的药理作用，如抗脑缺血再灌注损伤减少梗死面积，抗自由基形成，调节兴奋性氨基酸释放等。雌激素自身作为一种抗氧剂能够通过调节体内氧化还原平衡发挥神经保护作用。另外，雌激素在神经系统药理作用的发挥与其受体密不可分，经典的雌激素受体（ER-α, ER-β）主要位于细胞核内，二者均可在大脑皮质和海马表达：卵巢切除大鼠学习记忆能力降低的同时，ER-α在脑内皮质区和海马区表达也显著减少；ER-β基因敲除能够严重影响学习记忆行为、LTP和突触强度，该受体可能参与了高级脑功能的调节。NMDA受体作为与学习记忆密切相关的受体，与雌激素受体在海马区存在共表达。雌激素可能通过膜相关的雌激素受体介导机制快速激活ERK1/2信号转导通路，进一步诱导NMDA受体NR2B亚基磷酸化，激活NMDA受体，三者均会影响突触可塑性。本文就雌激素及其受体和Glu-NMDA受体通路与学习记忆的相关性进行综述。

关键词: 雌激素, 雌激素受体, 谷氨酸, N-甲基-D-天冬氨酸受体, 学习记忆

Abstract: Besides maintaining the female secondary sexual characteristics, estrogen also plays important roles in the nervous system, especially in the brain: it can protect tissue from cerebral ischemia reperfusion injury and reduce infarct area by suppressing free radical formation, and can also regulate the release of excitatory amino acids. As an antioxidant, estrogen can protect the nervous system by regulating the body’s redox homeostasis. In addition, estrogen can play its neuroprotective role through estrogen receptors (ER). ER-α and ER-β, two typical ER subtypes that are mainly located in the nucleus, are both expressed in the cerebral cortex and hippocampus. It has been found that ER-α level in the cortex and hippocampus of ovariotomy rats is decreased accompanying decreased learning and memory. LTP, synaptic density and learning and memory are all affected in ER-β gene knock-out mice. NMDA receptor is critical in learning and memory and is coexpressed in hippocampus with estrogen receptors. Estrogen may activate ERK1/2 signal transduction pathway through membrane estrogen receptors, thus inducing the phosphorylation of the NR2B subunit of NMDA receptor to activate NMDA receptor. In addition, the synaptic plasticity can be affected by estrogen and its receptors, as well as by NMDA receptor.

Key words: estrogen, estrogen receptor, glutamic acid, N-methyl-D-aspartic acid receptor(NMDA receptor), learning and memory

中图分类号:

张夏微, 张丹参. 雌激素和Glu-NMDA受体通路与学习记忆相关性的研究进展[J]. 神经药理学报, 2011, 1(6): 48-59.

ZHANG Xia-wei, ZHANG Dan-shen. Progress in Understanding the Relevance of Learning and Memory to Estrogen and Glu-NMDA Receptor Pathway[J]. ACTA NEUROPHARMACOLOGICA, 2011, 1(6): 48-59.

参考文献

[1] 杨华, 屈秋民, 郭峰. 雌激素在阿尔茨海默病患者的改变及其意义[J].中国神经精神疾病杂志, 2007, 33(3):179-182.

[2] Hironobu Sasano, Kazuhiro Takashashi, Fumitoshi Satoh, et al. Aromatase in the human central nervous system[J].Clin Endocrinol, 1998, 48(3):325-329.

[3] Josue G Yague, Inigo Azcoitia, Javier DeFelipe, et al. Aromatase expression in the normal and epileptic human hippocampus[J].Brain Res, 2010, 1315(22):41-52.

[4] Nader Shahrokhi, Mohammad K Haddad, Siavash Joukar, et al. Neuroprotective antioxidant effect of sex steroid hormones in traumatic brain injury[J].Pak J Pharm Sci, 2012, 25 (1):219-225.

[5] Spencer-Segal JL, Tsuda MC, Mattei L, et al. Estradiol acts via estrogen receptors alpha and beta on pathways important for synaptic plasticity in the mouse hippocampal formation[J]. Neuroscience, 2012, 27(202):131-146.

[6] Hyo-Seok Na, Hee-Pyeong Park, Chong-sung Kim, et al. 17β-Estradiol attenuates the activity of the glutamate transporter type 3 expressed in Xenopus oocytes[J]. Eur J Pharmacol, 2012, 676(1-3):20-25.

[7] Elisabetta Vegeto, Silvia Belcredito, Serena Ghisletti, et al. The endogenous estrogen status regulates microglia reactivity in animal models of neuroinflammation[J].Endocrinology, 2006, 147(5):2263-2272.

[8] 赵丕文.十种中药植物雌激素样作用及其机制的研究[D].北京:北京中医药大学,2007.

[9] 谈智, 王庭槐. 雌激素作用分子机制研究进展[J].中国病理生理杂志, 2003, 19(10):1422-1426.

[10] 梅春霞, 张吉强. 雌激素受体[J].生命的化学, 2010, 30(4):590-594.

[11] 张吉强, 蔡文琴. 脑内雌激素受体的研究进展[J].局解手术学杂志, 2009, 18 (1):1-2.

[12] 崔翔, 陶诗奇, 徐海伟, 等. ERβ调节海马依赖性高级认知功能的研究进展[J].神经解剖学杂志, 2012, 28(1):105-108.

[13] 安胜军, 张永祥. 雌激素受体亚型及其配体调节基因转录机制的研究[J].生理科学进展, 2002, 33(4):309-312.

[14] George G.J.M.Kuiper, Bo Carlsson, Kaj Grandien, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptor alpha and beta[J]. Endocrinology, 1997, 138(3):863-870．

[15] Zhang Ji-qiang, Cai Wen-qin, Zhou De-shan, et al. Distribution and differences of estrogen receptor beta immunoreactivity in the brain of adultmale and fe-male rats[J]. Brain Res, 2002, 935(1-2):73-80.

[16] 马路, 张吉强, 姚青. 雌激素合成酶与雌激素受体在神经干细胞及其分化后细胞内的表达[J].重庆医学, 2005, 34(4):560-562.

[17] 王尧, 杜子威. 神经生物化学与分子生物学[M].北京:人民卫生出版社, 1997:197-206.

[18] 李刚, 金蓓, 肖艳. 谷氨酸受体系统与药物作用的靶点[J].航空航天医药, 2005, 16 (3):51-54.

[19] 于明琨, 朱斌, 张光霁, 等.实验性颅脑损伤脑组织氨基酸含量变化及意义[J].中华神经外科杂志, 1994, 10(1) 34-37.

[20] Marco Milanese, Tiziana Bonifaeino, Simona Zappettini, et al. Glutamate release from astrocytic gliosomes under physiological and pathological conditions[J].Int Rev Neurobiol, 2009, 85:295-318.

[21] 潘静, 陈生弟. NMDA受体与神经退行性疾病的关系[J].上海交通大学学报(医学版), 2009, 29(1):98-100.

[22] Isoko Kuriyama, Naoki Asano, Ikuo Kato, et al. Dipeptide alcohol-based inhibitors of eukaryotic DNA polymerase alpha[J].Bioorg Med Chem, 2005, 13(6):2187-2196.

[23] 叶银萍. 双酚A对大鼠海马神经元树突发育的影响及其分子机制[D].金华:浙江师范大学, 2010.

[24] 刘智敏, 陈俊杰, 杨绍华. 谷氨酸受体分子的多样性及其分子机理[J].生物多样性, 1999, 7(1):52-59.

[25] 胡梅. NR2A和NR2B逆向调控神经元再生[D].南京:南京医科大学, 2007.

[26] 司文. NR2A转基因小鼠前额叶突触可塑性及其相关功能的研究[D].上海:华东师范大学, 2010.

[27] AM. Palmer, S. Gershon.老年性痴呆的神经元机制是胆碱能, 还是谷氨酸能?[J].生理科学进展, 1991, 22(2):111-113.

[28] 廖家万, 周兴海.突触后致密物与突触可塑性[J].河南职工医学院学报, 2007,19 (3):288-291.

[29] 陈燕. 神经元的突触可塑性与学习和记忆[J]. 生物化学与生物物理进展, 2008, 35(6): 610-619.

[30] 韩太真.关于长时程增强形成机理的研究进展[J].生理科学进展, 1994, 25 (l):60-63.

[31] 母得志, 姚裕家, 李炜如.兴奋性氨基酸及其受体与疾病[J].国外医学妇幼保健分册, 1996, 7(3):115-117.

[32] 张晓春, 左萍萍, 葛秦生.雌激素类药物对去卵巢大鼠认知功能的影响[J].生殖医学杂志, 2001, 10(3):135-140.

[33] 王兴华. 雌激素对慢性脑灌注不足的去卵巢大鼠神经保护作用的实验研究[D].重庆:第三军医大学, 2002.

[34] SHANG Xiu-li, ZHAO Jiu-han, CAO Yun-peng. Effects of synaptic plasticity regulated by 17β-estradiol on learning and memory in rats with Alzheimer’s disease[J]. Neurosci Bull April 1, 2010, 26(2): 133-139.

[35] Hirotaka Ishii, Keisuke Shibuya, Yoshihiro Ohta, et al. Enhancement of nitric oxide production by association of nitric oxide synthase with N-methyl-D-aspartate receptors via postsynaptic density 95 in genetically engineered Chinese hamster ovary cells:real-time fluoresence imaging using nitric oxide sensitive dye[J].J Neurochem, 2006, 96(6):1531-1539.

[36] Hideo Mukai , Tomokazu Tsurugizawa , Gen Murakami , et al. Rapid modulation of long-term depression and spinogenesis via synaptic estrogen receptors in hippocampal principal neurons[J].J Neurochem, 2007, 100(4):950-967.

[37] Takemasa Shiraishi, Kazuo Sasaki, Akira Nijima, et al. Leptin effects on feeding-related hypothalamic and peripheral neuronal activities in normal and obese rats[J]. Nutrition, 1999, 1(5):576-579.

[38] Lin S, Thomas TC, Storlien LH, et al. Development of high fat diet-induced obesity and leptin resistance in C57BL/6J mice[J].Int J Obes Relat Metab Disord, 2000, 2(4):639-646.

[39] Rivera HM, Bethea CL. Ovarian steroids increase spinogenetic proteins in the macaque dorsal raphe[J].Neuroscience, 2012, 208(4):27-40.

[40] Menahem Segal , Diane Murphy . Estradiol induces formation of dendritic spines in hippocampal neurons: functional correlates[J]. Horm Behav, 2001, 40(2):156-159.

[41] George A Bray. Afferent signals regulating food intake[J]. Proc Nutr Soc, 2000, 59 (3): 373-384.

[42] 聂伟, 张永祥, 周金黄. 雌激素对卵巢切除大鼠海马长时程增强的影响[J]. 中国神经科学杂志, 2001, 17(4):335-337.

[43] Barraclough DJ, Ingram CD, Brown MW. Chronic treatment with oestradiol does not alter in vitro LTP in subfield CA1 of the female rat hippocampus [J].Neuropharm- acology, 1999, 38(1):65-71.

[44] Mari Ogiue-Ikeda , Nobuaki Tanabe , Hideo Mukai , et al. Rapid modulation of synaptic plasti- city by estrogens as well as endocrine disrupters in hippocampal neurons[J].Brain Res Rev, 2008, 57(2):363-375.

[45] Yasushi Hojo , Gen Murakami , Hideo Mukai , et al. Estrogen synthesis in the brain--role in synaptic plasticity and memory[J].Mol Cell Endocrinol, 2008, 290(1-2):31-43.

[46] 商秀丽, 薛一雪, 蔡葵. 阿尔茨海默病大鼠海马N-甲基天冬氨酸受体和丝裂酶原激活蛋白激酶的表达[J].解剖学报, 2005, 36(3):241-245.

[47] Kramár EA, Babayan AH, Gall CM, et al. Estrogen promotes learning-related plasticity by modifying the synaptic cytoskeleton[J]. Neuroscience, 2012, 4522(12):1053-1056.

[48] Susan A Farr , William A Banks , John E Morley . Estradiol potentiates acetylcholine and glutamate-mediated post-trial memory processing in the hippocampus[J]. Brain Res, 2000, 864(2):263-269.

[49] Camila Castellan Cardoco, Victor Proenca Ricardo, Roberto Frussa-Fiho, et al. Effects of 17ß-estradiol on expression of muscarinic acetylcholine receptor subtypes and estrogen receptor alpha in rat hippocampus[J].Eur J Pharmacol, 2010, 634(1-3):192-200.

[50] Takuma K, Mizoquchi H, Funatsu Y, et al. Combination of chronic stress and ovariectomy causes conditioned fear memory deficits and hippocampal cholinergic neuronal loss in mice[J].Neuroscience, 2012, 207(5):261-273.

[51] Julie A Dumas , Amanda M Kutz , Magdalena R Naylor , et al. Estradiol treatment altered anticholiner- gic-related brain activation during working memory in postmenopausal women[J]. Neuroimage, 2012, 60(2):1394-1403.

[52] Danieli Brolo Martins , Cinthia Melazzo Mazzanti , Raqueli Teresinha França , et al. 17-β estradiol in the acetylcho- linesterase activity and lipid peroxidation in the brain and blood of ovariectomized adult and middle-aged rats[J]. Life Sci, 2012, 90(9-10):351-359.

[53] 陈多, 张冉, 吴春福. 雌激素改善学习记忆的机制[J].分子科学学报, 2002, 18(4): 230-234.

[54] Mark J Smith , Linda F Adams , Schmidt, et al. Effects of ovarian hormones on human cortical excitability[J]. Ann Neurol, 2002, 51(5):599-603.

[55] Ishii H, Tsurugizawa T, Ogiue-Ikeda M, et al. Local production of sex hormones and their modulation of hippocampal synaptic plasticity[J].Neuroscientist, 2007, 13 (4):323-334.

[56] Cynthia L Bethea , Arubala P Reddy . Ovarian steroids increase glutamatergic related gene expression in serotonin neurons of macaques[J].Mol Cell Neurosci, 2012, 49(3):251- 262.

[57] Weiland NG. Glutamic acid decarboxylase messenger ribonucleic acid is regulated by estradiol and progesterone in the hippocampus[J].Endocrinology, 1992, 131(6):2697-2702.

[58] Blutstein T, Devidze N, Choleris E, et al. Oestradiol up-regulates glutamine synthetase mRNA and protein expression in the hypothalamus and hippocampus: implications for a role of hormonally responsive glia in amino acid neurotransmission [J].J Neuroendocrinol, 2006, 18(9):692-702.

[59] Erik Hrabovszky , Imre Kalló, Gergely F Turi , et al. Expression of vesicular glutamate transporter-2 in gonadotrope and thyrotrope cells of the rat pituitary. Regulation by estrogen and thyroid hormone status[J]. Endocrinology, 2006, 147(8):3818-3825.

[60] Bereiter DA, Benetti AP. Amino acid release at the spinomedullary junction after inflammation of the TMJ region in male and female rats[J].Pain, 2006, 126(1- 3):175-183.

[61] Jacques Balthazart , Michelle Baillien , Gregory F Ball . Rapid control of brain aromatase activity by glutamatergic inputs[J].Endocrinology, 2006, 147(1):359-366.

[62] Catherine S Woolley, Nancy G Weiland, Bruce S Mcewen, et al. Estradiol increases the sensitivity of hippocampal CA1 pyramidal cells to NMDA receptor-mediated synaptic input: correlation with dendritic spine desity[J].J neurosci, 1997, 17(5):1848-1859.

[63] Michelle M Adam, Susan E Fink, William G Janssen, et al. Estrogen modulates synaptic N-methyl- D-aspartate receptor subunit distibution in the aged hippocampus[J].J Comp Neurol, 2004, 474(3):419-426.

[64] Hosein K Kia , Genvieve Yen , Christopher J Krebs , et al. Colocalization of estrogen receptor alpha and NMDA-2D mRNAs in amygdaloid and hypothalar-nic nuclei of the mouse brain[J]. Mol Brain Res, 2002, 104(1):47-54.

[65] 姚治芳, 李正莉, 童逸龄. NMDA受体1和雌激素受体在白细胞介素-2致痫大鼠脑内的表达变化和共存[J].解剖学报, 2007, 38(1):23-26.

[66] 姚国恩, 王景周, 陈曼娥. 血管性痴呆大鼠认知障碍的N-甲基-D-天冬氨酸受体体机制[J].中国临床康复, 2003, 7(10):1496-1498.

[67] Karen B Jelks , Rebecca Wylie , Candace L Floyd , et al. Estradiol targets synaptic proteins to induce glutamatergic synapse formation in cultured hippocampal neurons: critical role of estrogen receptor-alpha[J]. J Neurosci, 2007, 27(26):6903-6913.

[68] Morissette M, Le Saux M, Di Paolo T. Effect of oestrogen receptor alpha and beta agonists on brain N-methyl-D-aspartate receptors[J]. J Neuroendocrinol, 2008, 20(8):1006-1014.

[69] Xiao Xiao, Yang Yan, Zhang Yan, et al. Estrogen in the Anterior Cingulate Cortex Contributes to Pain-Related Aversion[J].Cereb Cortex, 2012, 24(6):673-679.

[70] 罗清清.雌激素和双酚A快速影响发育中大鼠海马NMDA受体活性及其机制[D].金华: 浙江师范大学, 2010.

[71] Xavier d'Anglemont de Tassigny , Celine Campagne , Sophie Steculorum , et al. Estradiol induces physical association of neuronal nitric oxide synthase with NMDA receptor and promotes nitric oxide formation via estrogen receptor activation in primary neuronal cultures[J].J Neurochem, 2009, 109(1):214-24.

[72] 张晓春, 左萍萍, 葛秦生. 雌激素类药物对去卵巢大鼠认知功能的影响[J].生殖医学杂志, 2001, 10(9):135-140.

[73] Eric M Snyder, Yi Nong, Claudia G Almeida, et al. Regulation of NMDA receptor trafficking by amyloid-beta[J]. Nat Neurosci, 2005, 8(8):1051-1058.

[74] Hans Zempel, Edda Thies, Eckhard Mandelkow, et al. Abeta oligomers cause localizedCa(2+) elevation，missorting of endogenous Tau into dendrites,Tauphosphorylation,and destruction of microtubules and spines[J]. J Neurosci, 2010, 30(36):11938-11950.

[75] Matos M, Augusto E, Oliveira CR, et al. Amyloid-beta peptide decreases glutamate uptake in cultured astrocytes: involvement of oxidative stress and mitogen-activated protein kinase cascades[J]. Neuroscience, 2008, 156(4): 898-910.

[76] Daniela Puzzo, Lucia Privitera, Elena Leznik, et al. Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus[J].J Neurosci, 2008, 28 (53):14537-14545.

[77] Connell BJ, Crosby KM, Richard MJ, et al. Estrogen-mediated neuroprotection in the cortex may require NMDA receptor activation[J].Neuroscience, 2007, 146(1): 160-169.

[78] 常全忠, 张淑玲. 雌激素对NMDA诱导离体大鼠海马神经元凋亡的作用[J].中国药理学通报, 2006, 22(4):456-460.

[79] Roberta Diaz Brinton , Pam Proffitt , Julie Tran , et al. Equilin, a principal component of the estrogen replacement therapy premarin, increases the growth of cortical neurons via an NMDA receptor-dependent mechanism[J]. Exp Neurol, 1997, 147(2):211-220.

[80] 王红, 王志安, 何瑞荣. 17β-雌二醇对大鼠脑片穹隆下器神经元放电活动的调变作用[J].生理学报, 2000, 52(6):515-518.