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Impact of progestins on estradiol potentiationof the glutamate calcium responseJon Nilsen and Roberta Diaz BrintonCADepartment of Molecular Pharmacology and Toxicology and the Program in Neuroscience,Univer sity of Southern California,Pharmaceutical Sciences Center,19 85 Zonal Avenue, Los Angeles, CA 9 0089, USACACorresponding AuthorReceived 13 February 2002; accepted 20 February 2002One mechanism by which estrogen may modulate cognitive func-tion is through p otentiation of glutamate-mediated rises in intra-cellular calcium ([Ca2þ]i) with resultant e¡ects on neuronalmorphology and signaling. Since progesterone is a component ofhormone replacement therapy (HRT), we sought to determinewhether therapeuticallyrelevant progestins attenuated or blockedestrogen potentiation of glutamate-induced [Ca2þ]irises. 17b-estradiol and progesterone, alone or in combination, signi¢cantlypotentiated therise in [Ca2þ]i.When co-administered, progesteroneattenuated the estrogen response to the level seen with proges-terone alone. In contrast, medroxyprogesterone acetate (MPA)had no e¡ect when administered alone and completely blockedthe 17b-estradiol-induced potentiation when co-administered.These results may have imp ortant implications for e¡ective use ofHRT to maintain cognitive function during menopause and aging.NeuroReport 13:825–830"c2002 Lippincott Williams & Wilkins.Key Words: Calcium; Cognitive function; Estrogen; Glutamate; Hormone replacement therapy; Neuron; ProgesteroneINTRODUCTIONIncreasing evidence indicates that estrogen regulates cogni-tive function and associated biochemical and genomicmechanisms of learning and memory [1]. In young women,fluctuations in estrogen level due to the menstrual cycle arepositively correlated with memory task performance withhigher estrogen levels associated with better cognitiveperformance [2]. In postmenopausal woman, estrogenreplacement therapy improves verbal and visual memory[3]. In addition to effects on cognition, estrogen replacementhas further been implicated in reducing the risk ofneurodegeneration and memory loss due to Alzheimer’sdisease (AD) [4,5]. The mechanism(s) underlying estrogeneffects on cognition centers on the NMDA glutamatereceptors, as blockade of NMDA receptors attenuates theeffects of estrogen on neuronal correlates of memory [6,7].Glutamate is the major excitatory neurotransmitter in themammalian CNS. At least three pharmacologically distinctionotropic receptors exist for glutamate: NMDA, kainateand AMPA receptors. Under normal physiological con-ditions, the NMDA receptor plays a vital role in the synapticplasticity thought to underlie learning and memory [8],most likely through its permeability to calcium (Ca2þ) [9],which acts as a second messenger. NMDA receptors must beactive in the hippocampal CA1 region in order to inducelong-term potentiation (LTP) a model of information storage[10]. Blockade of NMDA receptors causes behavioraldeficits similar to lesions of the hippocampus, as bothspatial reference and working memory are impaired [10].The case for an NMDA-receptor-dependent mechanismunderlying estrogen effects on memory function is sup-ported by morphological studies from both in vitro andin vivo preparations and by electrophysiological data fromhippocampal slice preparations in both dissociated hippo-campal neurons and hippocampal slices. A direct effect ofestrogens on neuronal process outgrowth was observed inour laboratory using dissociated cortical and hippocampalneurons, which was blocked by an NMDA receptorantagonist [6]. Woolley and colleagues have shown that17b-estradiol induces NMDA-receptor-dependent increasesin dendritic spines associated with an increase in synapses[11]. The excitatory nature of these estrogen-inducedsynapses is supported by a parallel increase in NMDAreceptor agonist binding sites and NMDAR1 subunitimmunoreactivity [12]. The morphological and biochemicalevidence which implicates a role of glutamate receptors inestrogen-induced neurotrophism is paralleled by electro-physiological evidence, as in slice preparations estradiolsignificantly increases both AMPA- and NMDA-generatedEPSPs [7].Although the receptors for estrogens and progestinsbelong to different nuclear receptor subfamilies andrecognize distinct hormone response elements, there isconsiderable cross talk between the estrogen and progestinsignaling pathways. Progestins have been shown to blockthe estrogen-stimulated expression of both c-fos andprogesterone receptor mRNAs in uterine cells [13]. Further-more, progestins and antiprogestins have been shown to0959- 4965"cLippincott Williams & Wilkins Vol 13 No 6 7 May 2002 825NEUROCHEMISTRY NEUROREPORTinhibit estrogen-stimulated uterine proliferation [13]. Thus,progestins have been added to hormone replacementtherapy (HRT), in part, to reduce the risk of uterine cancersassociated with unopposed estrogen [14]. In addition toprevention of endometrial hyperplasia, inclusion of proges-tins in HRT was thought to reduce estrogenic effects inbreast that are associated with increased risk of breastcancer [14]. Contrary to this long-held belief, a recent studyfound that an estrogen–progestin regimen increased cancerrisk beyond that associated with estrogen alone [15]. Thisemphasizes the necessity of studying the modulation ofestrogenic effects by progestins in various systems. Thepurpose of this study was to determine the effects of twowidely clinically used progesterones (progesterone andmedroxyprogesterone acetate) on potentiation by estrogenof the glutamate response in hippocampal neurons.MATERIALS AND METHODSAnimals: All studies were approved by the USC Instit-utional Review Board for animal care. Timed-pregnantSprague–Dawley rats were purchased from Harlan (India-napolis, IN). They were housed under controlled condi-tions of temperature (221C), humidity and light (14:10 hlight:dark) and water and food were available ad lib.Chemicals: All culture materials were purchased fromGibco BRL (Rockville, MD). All chemicals were purchasedfrom Sigma (St Louis, MO) unless otherwise noted. MPAwas obtained from Pharmacia and Upjohn Company(Peapack, NJ). Steroids were dissolved in ethanol at1 mg/ml and diluted in culture medium so that finalethanol concentration was o 0.001%.Neuronal culture: Primary cultures of dissociated hippo-campal neurons were performed as described previously[6]. Briefly, hippocampi were dissected from the brains ofE18 rat fetuses, treated with 0.02% trypsin in


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