Estrogen synthesis in the brain--role in synaptic plasticity and memory

Estrogen and androgen are synthesized from cholesterol locally in hippocampal neurons of adult animals. These neurosteroids are synthesized by cytochrome P450s and hydroxysteroid dehydrogenases (HSDs) and 5alpha-reductase. The expression levels of enzymes are as low as 1/200-1/50,000 of those in endocrine organs, however these numbers are high enough for local synthesis. Localization of P450(17alpha), P450arom, 17beta-HSD and 5alpha-reductase is observed in principal glutamatergic neurons in CA1, CA3 and the dendate gyrus. Several nanomolar levels of estrogen and androgen are observed in the hippocampus. Estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly in the hippocampus. Rapid action of 17beta-estradiol via membrane receptors is demonstrated for spinogenesis and long-term depression (LTD). The enhancement of LTD by 1-10nM estradiol occurs within 1 h. The density of spine is increased in CA1 pyramidal neurons within 2h after application of estradiol. The density of spine-like structure is, however, decreased by estradiol in CA3 pyramidal neurons. ERalpha, but not ERbeta, induces the same enhancement/suppression effects on both spinogenesis and LTD.     

Conformational signaling required for synaptic plasticity by the NMDA receptor complex

The NMDA receptor (NMDAR) is known to transmit important information by conducting calcium ions. However, some recent studies suggest that activation of NMDARs can trigger synaptic plasticity in the absence of ion flow. Does ligand binding transmit information to signaling molecules that mediate synaptic plasticity? Using Förster resonance energy transfer (FRET) imaging of fluorescently tagged proteins expressed in neurons, conformational signaling is identified within the NMDAR complex that is essential for downstream actions. Ligand binding transiently reduces FRET between the NMDAR cytoplasmic domain (cd) and the associated protein phosphatase 1 (PP1), requiring NMDARcd movement, and persistently reduces FRET between the NMDARcd and calcium/calmodulin-dependent protein kinase II (CaMKII), a process requiring PP1 activity. These studies directly monitor agonist-driven conformational signaling at the NMDAR complex required for synaptic plasticity.Agonist binding to the NMDAR is required for two major forms of synaptic plasticity: long-term potentiation (LTP) and long-term depression (LTD) (1). Surprisingly, activation of NMDARs can produce plasticity in opposite directions, with LTP enhancing transmission and LTD reducing transmission. A model was developed (2, 3) to explain how activation of NMDAR could produce these opposing phenomena: strong stimuli during LTP induction drive a large flux of Ca²⁺ through NMDARs, leading to a large increase in intracellular calcium ion concentration ([Ca²⁺]_i) that activates one series of biochemical steps leading to synaptic potentiation; a weaker stimulus during LTD induction drives a more reduced flux of Ca²⁺ through NMDARs, producing a modest increase in [Ca²⁺]_i that activates a different series of biochemical steps, leading to synaptic depression. However, this model is not consistent with recent studies suggesting that no change in [Ca²⁺]_i is required for LTD, and instead invokes metabotropic signaling by the NMDAR (4). Studies supporting an ion-flow-independent role for NMDARs in LTD (4–7) and other processes (7–13) stand in contrast to studies proposing that flow of Ca²⁺ through NMDAR is required for LTD (14) (see ref. 15 for additional references). An important test of an ion-flow-independent model would be to measure directly signaling actions by NMDARs in the absence of ion flow.     

胃癌雌激素受体和孕激素受体的检测及临床意义

目的：为了研究雌激素受体（Ｅｓｔｒｏｇｅｎ ｒｅｃｅｐｔｏｒ,ＥＲ）的孕激素受体（Ｐｒｏｇｅｓｔｅｒｏｎｅ ｒｅｃｅｐｔｏｒ,ＰｇＲ）在胃癌中的表达以及与临床病理学之间的关系。方法：我们采用免疫组织化学法对９１例胃癌作了测定。结果：９１例胃癌的ＥＲ,ＰｇＲ阳性率分别为３９．６％,４１．８％。在９１例胃癌中,分化好的腺癌细胞ＥＲ,ＰｇＲ阳性率均为４７．９％,高于分化差的癌细胞的ＥＲ,ＰｇＲ阳性率（３     

Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca²⁺ levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca²⁺-levels to RA synthesis remains unknown. Here we identify the Ca²⁺-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca²⁺-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity.Synaptic plasticity, a fundamental feature of the nervous system, is defined as modification of synaptic strength based on experience and activity history. Homeostatic synaptic plasticity is a type of compensatory mechanism activated during chronic elevation or reduction of network activity to modulate synaptic strength in the opposite direction (for example, reduced network activity leads to increased synaptic strength) (1, 2). Retinoic acid (RA) is a key signaling molecule in a form of homeostatic synaptic plasticity induced by reduced excitatory synaptic activity (3–5). Prolonged inhibition of excitatory synaptic transmission leads to a compensatory increase in synaptic excitation and a decrease in synaptic inhibition (4, 5). Both of these processes require RA synthesis. It also has been shown that dendritic Ca²⁺ levels directly govern the synthesis of RA; basal Ca²⁺ levels maintained by normal synaptic transmission are sufficient to suppress RA synthesis. Upon synaptic activity inhibition, reduced Ca²⁺ levels de-repress RA synthesis and activate RA-dependent homeostatic synaptic mechanisms (6). Thus, a Ca²⁺-dependent signaling molecule that is sensitive to changes in basal Ca²⁺ levels must be involved in synaptic RA signaling.Ca²⁺-dependent protein kinases and phosphatases are critical components of signaling pathways involved in synaptic plasticity (7, 8). For example, regulation of the phosphorylation of key serine residues in the C-terminal sequences of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type glutamate receptor (AMPAR) subunit GluA1 by kinases (i.e., PKA, PKC, and CaMKII) and phosphatases [i.e., calcineurin (CaN) and PP2A] is thought to play major roles in governing AMPAR trafficking in and out of the synaptic membrane and to mediate the expression of well-established forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD) (9–12). A recent study examining the stoichiometry of AMPAR phosphorylation revealed surprisingly low levels of phosphorylated GluA1 in neurons (13), however, suggesting that the phosphorylation of AMPARs might not be involved in homeostatic plasticity, and that other mechanisms may be in play.In the present study, we identified CaN as the Ca²⁺-dependent signaling molecule that regulates RA synthesis in neurons in an activity-dependent manner. Inhibition of CaN activity triggers RA synthesis, suggesting that basal CaN activity, supported by normal synaptic transmission, is sufficient to suppress RA synthesis in an active neural network. In CaN-deficient neurons, synaptic activity blockade-induced RA-dependent forms of homeostatic synaptic plasticity are absent. Similar to direct RA application, CaN inhibition enhances excitatory synaptic transmission and reduces inhibitory synaptic transmission. Blocking RA synthesis or genetic deletion of the RA receptor RARα prevents CaN inhibitor-induced regulation of synaptic strength, indicating that CaN acts upstream of RA. Importantly, neurons bearing GluA1 S831A or S845A knockin (KI) mutations, which eliminate phosphorylation at these two serine residues, respond normally to CaN inhibitors and RA treatment. Taken together, our results indicate that CaN participates in RA-dependent homeostatic synaptic plasticity through regulation of RA synthesis independent of the modulation of GluA1 phosphorylation.     

Estrogen dependent signaling in reproductive tissues - a role for estrogen receptors and estrogen related receptors

Estrogens play a fundamental role in the development and normal physiological function of multiple tissue systems and have been implicated in the ontogeny of cancers. The biological effects of estrogens are classically mediated via interaction with cognate nuclear receptors. The relative expression of ER subtypes/variants varies between cells within different tissues and this alters the response to natural and synthetic ligands. This review focuses on the role of estrogen and estrogen related receptors in reproductive tissues.     

Distinct kinetics of synaptic structural plasticity,memory formation,and memory decay in massed and spaced learning

Long-lasting memories are formed when the stimulus is temporally distributed (spacing effect). However, the synaptic mechanisms underlying this robust phenomenon and the precise time course of the synaptic modifications that occur during learning remain unclear. Here we examined the adaptation of horizontal optokinetic response in mice that underwent 1 h of massed and spaced training at varying intervals. Despite similar acquisition by all training protocols, 1 h of spacing produced the highest memory retention at 24 h, which lasted for 1 mo. The distinct kinetics of memory are strongly correlated with the reduction of floccular parallel fiber–Purkinje cell synapses but not with AMPA receptor (AMPAR) number and synapse size. After the spaced training, we observed 25%, 23%, and 12% reduction in AMPAR density, synapse size, and synapse number, respectively. Four hours after the spaced training, half of the synapses and Purkinje cell spines had been eliminated, whereas AMPAR density and synapse size were recovered in remaining synapses. Surprisingly, massed training also produced long-term memory and halving of synapses; however, this occurred slowly over days, and the memory lasted for only 1 wk. This distinct kinetics of structural plasticity may serve as a basis for unique temporal profiles in the formation and decay of memory with or without intervals.During learning, memories are formed in a specific population of neuronal circuits and are consolidated for persistence (1, 2). These memory processes are supported by discrete subcellular events such as reversible modifications in the efficacy of synaptic transmission (3–5) or persistent structural modifications in the size and number of synaptic connections (6–8). However, how these synaptic modifications relate to the dynamics of formation and decay of memories in behaving animals remains elusive. Memory formation and its persistence are also sensitive to the temporal features of stimulus presentation, as observed in the well-known “spacing effect.” Training trials that include resting intervals between them (spaced training) produce stronger and longer-lasting memories than do the same number of trials with no intervals (massed training) (9). The spacing effect has been observed in a variety of explicit and implicit memory tasks (10–13), and the molecular mechanisms supporting this phenomenon have been reported (14–18). Various intracellular signaling molecules such as CREB (19), mitogen-activated protein (MAP) kinase (20, 21), and PKA (22, 23) underlie the spacing effect and are implicated in the remodeling of neuronal structures (23). In vitro studies showed that spaced stimuli induced the protrusion of new filopodia (20) and the recruitment of new synapses (24) in hippocampal neurons. However, despite the existence of numerous behavioral and molecular studies, no conjoint study has elucidated the synaptic correlates that underpin the expression of the spacing effect during learning. Here we studied the temporal evolution and decay of memory and its correlation with synaptic modifications during learning with distinct temporal patterns of training.We used an adaptation of the horizontal optokinetic response (HOKR), which is a simple model of cerebellum-dependent motor learning. It is a compensatory eye movement for stabilization of the visual image on the retina during horizontal motion of the surroundings. A surrounding that oscillates horizontally at a given frequency causes retinal slips in naive animals and facilitates HOKR 1 h after training (HOKR adaptation) (25–27). The amount of adaptation can be quantitatively monitored, and the flocculus (Fl), which is a phylogenetically preserved cerebellar lobule, is involved in the adaptation of the HOKR (28, 29). These features render this paradigm as an experimental model, useful for investigating neural correlates and mechanisms involved in motor learning. In a previous study, we showed that the short-term adaptation of HOKR induced by 1-h training was accompanied by a rapid and transient reduction (28%) in the number of AMPA receptors (AMPARs) in parallel fiber (PF) to Purkinje cell (PC) synapses, whereas the long-term adaptation induced by repeated 1-h training over 5 d was accompanied by a slowly developing reduction (45%) of PF–PC synapses (30). Despite recent controversies on the role of long-term depression (LTD) and a postulated role of long-term potentiation in cerebellar motor learning (31–33), this study first showed that LTD as a form of reduced AMPARs in PF–PC synapses does occur in physiological learning.In the present study, we further examined how the spacing effect is correlated with the structural plasticity in PF–PC synapses. We showed that spaced training including 1-h intervals induced stable long-lasting memories within 4 h after the training, which was accompanied by a rapid and long-lasting (>1 mo) reduction of PF–PC synapses after a transient reduction in AMPAR density and shrinkage of PF–PC synapses and PC spines. One hour of massed training also induced a gradual reduction of the PF–PC synapses, which reached the same level as that observed for the spaced training 5 d later but recovered faster within 10 d. The time course corresponded well with the slower establishment and quicker decay of long-lasting memory induced by massed training. The tight correlation observed between the structural modifications and the kinetics of long-lasting memory pinpoints the distinct temporal regulation of synaptic connections as a mechanism underlying the spacing effect.     

Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism

Intrastriatal transplantation of dopaminergic neurons can restore striatal dopamine levels and improve parkinsonian deficits, but the mechanisms underlying these effects are poorly understood. Here, we show that transplants of dopamine neurons partially restore activity-dependent synaptic plasticity in the host striatal neurons. We evaluated synaptic plasticity in regions distal or proximal to the transplant (i.e., dorsolateral and ventrolateral striatum) and compared the effects of dopamine- and serotonin-enriched grafts using a rat model of Parkinson disease. Naïve rats showed comparable intrinsic membrane properties in the two subregions but distinct patterns of long-term synaptic plasticity. The ventrolateral striatum showed long-term potentiation using the same protocol that elicited long-term depression in the dorsolateral striatum. The long-term potentiation was linked to higher expression of postsynaptic AMPA and N2B NMDA subunits (GluN2B) and was dependent on the activation of GluN2A and GluN2B subunits and the D1 dopamine receptor. In both regions, the synaptic plasticity was abolished after a severe dopamine depletion and could not be restored by grafted serotonergic neurons. Solely, dopamine-enriched grafts could restore the long-term potentiation and partially restore motor deficits in the rats. The restoration could only be seen close to the graft, in the ventrolateral striatum where the graft-derived reinnervation was denser, compared with the distal dorsolateral region. These data provide proof of concept that dopamine-enriched transplants are able to functionally integrate into the host brain and restore deficits in striatal synaptic plasticity after experimental parkinsonism. The region-specific restoration might impose limitations in symptomatic improvement following neural transplantation.Nonpharmacological dopamine (DA) replacement approaches to the therapy of Parkinson disease (PD) focus on the transplantation of DA-producing neurons into the striatum. Parkinson disease is indeed viewed as the disease of choice to develop intracerebral transplantation therapies, and promising results have been obtained both in experimental models and in some patients using embryonic DA neurons (1, 2). Embryonic DA neurons are able to innervate the host striatum, release DA, and reverse alterations in neuropeptide expression after a parkinsonian lesion (3). There is a continuous debate about whether these effects are sufficient for transplanted neurons to partially restore clinical symptoms or whether other underlying mechanisms also are required. In particular, a functional integration of the graft into the host microcircuits, with bidirectional synaptic contacts between the host and grafted neurons, may give superior therapeutic benefit than a mere neurochemical restoration. Transplanted DA neurons are able to form synapses with the surrounding striatal medium-sized spiny neurons (MSNs) (4) and receive innervation from the host neurons with bidirectional synaptic interactions (5–7). It is, however, unknown whether these plastic changes are sufficient to restore the basic functional properties of the host neurons essential for corticostriatal control of movements (8). This study attempts to understand whether neural transplants have the ability to restore activity-dependent synaptic plasticity in the host corticostriatal pathway.We have herein investigated corticostriatal plasticity after transplantation of DA and 5-HT neurons in host MSNs in an experimental model of PD. Dopamine is critical for inducing long-term striatal plasticity, i.e., long-term potentiation (LTP) and long-term depression (LTD) in MSNs (9). The changes are mediated by the activation of ionotropic glutamate receptors, i.e., alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors, as well as by the activation of DA receptors. Consequently, animal models of severe DA denervation have demonstrated a loss of both forms of corticostriatal plasticity in the dorsolateral (DL) striatum (10, 11). A partial DA denervation, on the other hand, spares LTD in the DL striatum (12). Also clinical studies have revealed an impairment of synaptic plasticity in the corticostriatal pathway (13).Using an experimental model of PD, we here demonstrate that transplanted DA neurons are efficient in restoring corticostriatal plasticity in the densely innervated area close to the graft whereas more sparsely innervated areas remain unaffected. This restoration is in contrast to the effect of transplanted 5-HT neurons that were unable to restore any type of plasticity.     

The Expression of Estrogen Receptor is Dependent on the Estrogen Level and Associated with Cholesterol - Rich Diet in Female Rat''''s Heart and Vascular Endothelial Cells

Objective To study the effects of estrogen level and cholesterol - rich diet on the expression of estrogen receptor (ER) in cardiovascular tissues including vascular endothelial cells (VEC) of female rats. Methods The receptor binding assay (RBA) was adopted to measure the estrogen receptor level in aortic wall, heart and vascular endothelial cells of female rats on a cholesterol - rich diet. A ra-dioimmunoassay was employed to measure the level of serum estradiol. Results The number of ER significantly decreased in hearts, aorta and vascular endothelial cells in the ovariectomized rats and the rats on a cholesterol - rich diet. In contrast, the administration of estrogen somewhat restored the expression of ER. Conclusions For female rats, the level of estrogen affects the expression of ER in cardiovascular system. The number of ER decreases along with the decrease in the level of estrogen. A cholesterol - rich diet also can decrease the expression of ER in cardiovascular system of female rats.     

Estrogen and progesterone receptor isoforms expression in the stomach of Mongolian gerbils

AIM： We studied the estrogen receptor （ER） and progesterone receptor （PR） isoforms expression in gastric antrum and corpus of female gerbils and their regulation by estradiol （E2） and progesterone （P4）.
METHODS： Ovariectomized adult female gerbils were subcutaneously treated with E2, and E2 ＋ P4. Uteri and stomachs were removed, the latter were cut along the greater curvature, and antrum and corpus were excised. Proteins were immunoblotted using antibodies that recognize ER-alpha, ER-beta, and PR-A and PR-B receptor isoforms. Tissues from rats treated in the same way were used as controls.
RESULTS： Specific bands were detected for ERalpha （68 KDa）, and PR isoforms （85 and 120 KDa for PR-A and PR-B isoforms, respectively） in uteri, gastric antrum and corpus. We could not detect ER-beta isoform. PR isoforms were not regulated by E2 or P4 in uterus and gastric tissues of gerbils. ER-alpha isoform content was significantly down-regulated by E2 in the corpus, but not affected by hormones in uterus and gastric antrum.
CONCLUSION： The presence of ER-alpha and PR isoforms in gerbils stomach suggests that E2 and P4 actions in this organ are in part mediated by their nuclear receptors.     

Estrogen receptor determinations in primary breast cancer

Summary The present study describes the estrogen receptor (ER) detection by an immunocytochemical assay kit (ER-ICA) on cryostat sections of 78 primary breast carcinomas. Results are compared with quantitatively measured ER levels, which were obtained by the dextran-coated charcoal (DCC) method. An excellent overall correlation between the logarithm of the ER levels, estimated by this technique, and the semiquantitative immunocytochemical evaluation was found, i.e. r=0.73. Since the ER-ICA can be easily handled without radioactivity being involved and since it is more representative of the total tumor, we conclude (as other groups before us) that the ER-ICA is an easy-to-handle and reliable technique presenting many advantages over the DCC method.Dedicated to Prof. Dr. H.-G. Hillemanns on his 65th birthday     

Effects of Estrogen Level on the Function of Vascular Endothelial Cells and Expression of Vascular Cell Adhesion Molecule-1(?)

Objectives To ob-serve the effect of different estrogen levels on the secretory function of vascular endothelial cells of female rats, and study the effect of modulation of estrogen level on the expression of vascular cell adhesion molecule - 1 and the concentration of estrogen receptor in vascular endothelial cells. Methods Radioim-munology was used to measure the serum concentration of endothelin and PGI2, and copper - cadmium reduction was employed to measure the serum content of nitrogen monoxide. Radioligand binding and flowcy-tometry were used to measure the expression of estrogen receptor and vascular cell adhesion molecule (VCAM - 1) of vascular endothelial cells respectively. Results 1. The serum concentration of nitric oxide and PGI2 decreased when the ovaries of female rats were removed. In ovariectomized rats, given estrogen, the concentration rose ( P < 0. 05), but the plasma concentration of endothelin was adverse to it. 2. The concentration of estrogen receptor of vascular endothelial cel     

Estrogen receptor beta mediates gender differences in ischemia/reperfusion injury

Under hypercontractile conditions associated with increased intracellular calcium, male hearts show enhanced ischemia/reperfusion injury compared to female hearts. Our aim in this study was to identify the specific estrogen receptor involved in this gender difference. Following brief treatment with isoproterenol, isolated mouse hearts were subjected to ischemia and reperfusion. Postischemic contractile function and infarct size were measured in wild-type (WT) male and female hearts, and female hearts lacking functional alpha estrogen receptor (alpha ERKO), or the beta estrogen receptor (beta ERKO). WT male hearts exhibited significantly less functional recovery and more necrosis than WT females. alpha ERKO female hearts exhibited ischemia/reperfusion injury similar to that observed in WT females, whereas beta ERKO females exhibited significantly less functional recovery than WT females and were similar to WT males. These data suggest that estrogen, through the beta-estrogen receptor, plays a role in the protection observed in the female heart. Furthermore, we identified genes that were differentially expressed in beta ERKO female hearts compared to alpha ERKO and WT female hearts, and found altered expression of a number of metabolism genes, which may be important in ischemic injury. We further showed that WT female hearts have increased ratio of carbohydrate to fatty acid metabolism relative to WT males.     

Estrogen and estrogen receptor signaling promotes allergic immune responses: Effects on immune cells,cytokines, and inflammatory factors involved in allergy

Hypersensitivity occurs when the body is stimulated by an antigen, resulting in an immune response, and leads to a physiological disorder or abnormal tissue trauma. Various immune cells, cytokines, and inflammatory mediators are involved in the immune responses related to allergic diseases, which are the core of anaphylaxis. Estrogen receptors are widely distributed in immune cells, which combine with estrogen and participate in allergic responses by affecting immune cells, cytokines, and inflammatory factors. We aimed to summarize the association between estrogen and allergic reactions to provide a scientific basis for understanding and studying the mechanisms of allergic diseases.     

Estrogen receptor status and adjuvant polychemotherapy or antiestrogen therapy in patients with high-risk breast cancer

Summary This pilot study includes 115 consecutive patients admitted in the period from 1978 to 1981. Patients eligible for this study were at high risk according to the TNM classification with stages pT1-pT3 and pN+, MO. Primary therapy included modified radical mastectomy and axillary-node clearance, one or more ipsilateral nodes being involved in routine histology. All tumors were assayed for estrogen and progesterone receptors. According to the result of the estrogen receptor assay, estrogen-receptor-positive patients were treated with Tamoxifen 30 mg/day for a period of 2 years. Estrogen-receptor-negative patients were treated with cytoxan, methotrexate, and 5-fluorouracil or adriblastin, cytoxan. After a median observation time of 36 months, overall there have been 31 recurrences: 9=17.3% in the estrogen-receptor-positive group and 22=34.9% in the estrogen-receptor-negative group. The analysis of different subgroups showed no significant differences, either in relation to axillary lymph-node status or in relation to menopausal status in the endocrine-treated compared with the polychemotherapy group. This result suggests, especially in the subgroup of patients with involvement of one to three axillary nodes, that estrogen-receptor-positive and estrogen-receptor-negative patients should be considered as separate groups when adjuvant therapy is indicated. Possibly hormone-receptor-positive patients may benefit from endocrine therapy and do not need polychemotherapy.     

Role of the calcium-binding protein parvalbumin in short-term synaptic plasticity

GABAergic (GABA = gamma-aminobutyric acid) neurons from different brain regions contain high levels of parvalbumin, both in their soma and in their neurites. Parvalbumin is a slow Ca(2+) buffer that may affect the amplitude and time course of intracellular Ca(2+) transients in terminals after an action potential, and hence may regulate short-term synaptic plasticity. To test this possibility, we have applied paired-pulse stimulations (with 30- to 300-ms intervals) at GABAergic synapses between interneurons and Purkinje cells, both in wild-type (PV+/+) mice and in parvalbumin knockout (PV-/-) mice. We observed paired-pulse depression in PV+/+ mice, but paired-pulse facilitation in PV-/- mice. In paired recordings of connected interneuron-Purkinje cells, dialysis of the presynaptic interneuron with the slow Ca(2+) buffer EGTA (1 mM) rescues paired-pulse depression in PV-/- mice. These data show that parvalbumin potently modulates short-term synaptic plasticity.     

Role of Estrogen in Alcohol Promotion of Breast Cancer and Prolactinomas

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was Dipak K. Sarkar. The presentations were (1) Dual role of estrogen as hormone and carcinogen in mammary carcinogenesis, by Joachim G. Liehr; (2) Alcohol and breast cancer: Studies using animals, by Keith W. Singletary; and (3) Evaluation of the role of estrogen in mediation of ethanol effect on prolactinoma: Studies using animals, by Dipak K. Sarkar.