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ABSTRACT: OBJECTIVE: Low dose exposure to endocrine disrupters (environmental chemicals) may induce hormone-like effects on wildlife and humans. bisphenol A (BPA) might disturb the neuronal signaling regulated by endogenous estrogens. We investigated the rapid modulation effects of 10nM BPA, a typical endocrine disruptor, on long-term depression (LTD) of adult rat hippocampal slices. METHOD: LTD was induced by a transient perfusion of 30 µM NMDA for 3 min. And measured with multielectrode probes. RESULTS: A 30 min perfusion of 10 nM BPA rapidly enhanced LTD in CA1, however, BPA suppressed LTD in dentate gyrus (DG). An ERRγ antagonist, 4-OH-tamoxifen, suppressed LTD in CA1 and DG. Inhibitor of estrogen receptor ICI 182,780 did not disturb BPA effects. On the other hand, tributyltin (TBT), another endocrine disruptor, did not have any effect on LTD in CA1 and DG. CONCLUSION: ERRγ, but not estrogen receptors, is a high affinity BPA receptor in LTD processes, since the effect of BPA on LTD was suppressed by an ERRγ antagonist. A possible mechanisms of BPA-induced enhancement of LTD could be described with ERRγ, MAPK activation and phosphorylation of MMDA receptors.
Neuro endocrinology letters 04/2013; 34(2):129-134. · 1.30 Impact Factor
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ABSTRACT: Estrogen, a class of female sex steroids, is neuroprotective. Estrogen is synthesized in specific areas of the brain. There is a possibility that the de novo synthesized estrogen exerts protective effect in brain, although direct evidence for the neuroprotective function of brain-synthesized estrogen has not been clearly demonstrated. Methylmercury (MeHg) is a neurotoxin that induces neuronal degeneration in the central nervous system. The neurotoxicity of MeHg is region-specific, and the molecular mechanisms for the selective neurotoxicity are not well defined. In this study, the protective effect of de novo synthesized 17β-estradiol on MeHg-induced neurotoxicity in rat hippocampus was examined.
Neurotoxic effect of MeHg on hippocampal organotypic slice culture was quantified by propidium iodide fluorescence imaging. Twenty-four-hour treatment of the slices with MeHg caused cell death in a dose-dependent manner. The toxicity of MeHg was attenuated by pre-treatment with exogenously added estradiol. The slices de novo synthesized estradiol. The estradiol synthesis was not affected by treatment with 1 µM MeHg. The toxicity of MeHg was enhanced by inhibition of de novo estradiol synthesis, and the enhancement of toxicity was recovered by the addition of exogenous estradiol. The neuroprotective effect of estradiol was inhibited by an estrogen receptor (ER) antagonist, and mimicked by pre-treatment of the slices with agonists for ERα and ERβ, indicating the neuroprotective effect was mediated by ERs.
Hippocampus de novo synthesized estradiol protected hippocampal cells from MeHg-induced neurotoxicity via ERα- and ERβ-mediated pathways. The self-protective function of de novo synthesized estradiol might be one of the possible mechanisms for the selective sensitivity of the brain to MeHg toxicity.
PLoS ONE 01/2013; 8(2):e55559. · 4.09 Impact Factor
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ABSTRACT: We demonstrated the rapid effects of 10nM bisphenol A (BPA) on the spinogenesis of adult rat hippocampal slices. The density of spines was analyzed by imaging Lucifer Yellow-injected CA1 neurons in slices. Not only the total spine density but also the head diameter distribution of spine was quantitatively analyzed. Spinogenesis was significantly enhanced by BPA within 2h. In particular, the density of middle-head spine (with head diameter of 0.4-0.5μm) was significantly increased. Hydroxytamoxifen, an antagonist of both estrogen-related receptor gamma (ERRγ) and estrogen receptors (ERα/ERβ), blocked the BPA-induced enhancement of the spine density. However, ICI 182,780, an antagonist of ERα/ERβ, did not suppress the BPA effects. Therefore, ERRγ is deduced to be a high affinity receptor of BPA, responsible for modulation of spinogenesis. The BPA-induced enhancement of spinogenesis was also suppressed by MAP kinase inhibitor, PD98059, and the blocker of NMDA receptors, MK-801. Washout of BPA for additional 2h after 2h BPA treatment abolished the BPA-induced enhancement of spinogenesis, suggesting that the BPA effect was reversible. ERRγ was localized at synapses as well as cell bodies of principal neurons. ERRγ at synapses may contribute to the observed rapid effect. The level of BPA in the hippocampal slices was determined by mass-spectrometric analysis.
Molecular and Cellular Endocrinology 04/2012; 351(2):317-25. · 4.19 Impact Factor
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ABSTRACT: Modulation of dendritic spines under acute stress is attracting much attention. Exposure to acute stress induces corticosterone (CORT) secretion from the adrenal cortex, resulting in rapid increase of CORT levels in plasma and the hippocampus.
Here we demonstrated the mechanisms of rapid effect (∼1 h) of CORT on the density and morphology of spines by imaging neurons in adult male rat hippocampal slices. The application of CORT at 100-1000 nM induced a rapid increase in the density of spines of CA1 pyramidal neurons. The density of small-head spines (0.2-0.4 µm) was increased even at low CORT levels (100-200 nM). The density of middle-head spines (0.4-0.5 µm) was increased at high CORT levels between 400-1000 nM. The density of large-head spines (0.5-1.0 µm) was increased only at 1000 nM CORT. Co-administration of RU486, an antagonist of glucocorticoid receptor (GR), abolished the effect of CORT. Blocking a single kinase, such as MAPK, PKA, PKC or PI3K, suppressed CORT-induced enhancement of spinogenesis. Blocking NMDA receptors suppressed the CORT effect.
These results imply that stress levels of CORT (100-1000 nM) drive the spinogenesis via synaptic GR and multiple kinase pathways.
PLoS ONE 01/2012; 7(4):e34124. · 4.09 Impact Factor
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ABSTRACT: The hippocampus synthesizes estrogen and androgen in addition to the circulating sex steroids. Synaptic modulation by hippocampus-derived estrogen or androgen is essential to maintain healthy memory processes. Rapid actions (1-2h) of 17β-estradiol (17β-E2) occur via synapse-localized receptors (ERα or ERβ), while slow genomic E2 actions (6-48h) occur via classical nuclear receptors (ERα or ERβ). The long-term potentiation (LTP), induced by strong tetanus or theta-burst stimulation, is not further enhanced by E2 perfusion in adult rats. Interestingly, E2 perfusion can rescue corticosterone (stress hormone)-induced suppression of LTP. The long-term depression is modulated rapidly by E2 perfusion. Elevation of the E2 concentration changes rapidly the density and head structure of spines in neurons. ERα, but not ERβ, drives this enhancement of spinogenesis. Kinase networks are involved downstream of ERα. Testosterone (T) or dihydrotestosterone (DHT) also rapidly modulates spinogenesis. Newly developed Spiso-3D mathematical analysis is used to distinguish these complex effects by sex steroids and kinases. It has been doubted that the level of hippocampus-derived estrogen and androgen may not be high enough to modulate synaptic plasticity. Determination of the accurate concentration of E2, T or DHT in the hippocampus is enabled by mass-spectrometric analysis in combination with new steroid-derivatization methods. The E2 level in the hippocampus is approximately 8nM for the male and 0.5-2nM for the female, which is much higher than that in circulation. The level of T and DHT is also higher than that in circulation. Taken together, hippocampus-derived E2, T, and DHT play a major role in modulation of synaptic plasticity.
The Journal of steroid biochemistry and molecular biology 10/2011; 131(1-2):37-51. · 2.66 Impact Factor
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ABSTRACT: We investigated rapid protection effect by estradiol on corticosterone (CORT)-induced suppression of synaptic transmission. Rapid suppression by 1 μM CORT of long-term potentiation (LTP) at CA3-CA1 synapses was abolished via coperfusion of 1 nM estradiol. N-methyl-D-aspartate (NMDA) receptor-derived field excitatory postsynaptic potential (NMDA-R-fEPSP) was used to analyze the mechanisms of these events. Estradiol abolished CORT-induced suppression of NMDA-R-fEPSP slope. This CORT-induced suppression was abolished by calcineurin inhibitor, and the rescue effect by estradiol on the CORT-induced suppression was inhibited by mitogen-activated protein (MAP) kinase inhibitor. The CORT-induced suppressions of LTP and NMDA-R-fEPSP slope were abolished by glucocorticoid receptor (GR) antagonist, and the restorative effects by estradiol on these processes were mimicked by estrogen receptor α (ERα) and ERβ agonists. Taken together, estradiol rapidly rescued LTP and NMDA-R-fEPSP slope from CORT-induced suppressions. A GR→calcineurin pathway is involved in these suppressive effects. The rescue effects by estradiol are driven via ERα or ERβ→MAP kinase pathway. Synaptic/extranuclear GR, ERα, and ERβ probably participate in these rapid events. Mass-spectrometric analysis determined that acute hippocampal slices used for electrophysiological measurements contained 0.48 nM estradiol less than exogenously applied 1 nM. In vivo physiological level of 8 nM estradiol could protect the intact hippocampus against acute stress-induced neural suppression.
Cerebral Cortex 07/2011; 22(4):926-36. · 6.54 Impact Factor
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ABSTRACT: Accurate 3D determination of postsynaptic structures is essential to our understanding memory-related function and pathology in neurons. However, current methods of spine analysis require time-consuming and labor-intensive manual spine identification in large image data sets. Therefore, a realistic implementation of algorithm is necessary to replace manual identification. Here, we describe a new method for the automated detection of spines and dendrites based on analysis of geometrical features. Our "Spiso-3D" software carries out automated dendrite reconstruction and spine detection using both eigenvalue images and information of brightness, avoiding detection of pseudo-spines. To demonstrate the potential application of Spiso-3D automated analysis, we distinguished the rapid effects of androgen and estrogen on rapid modulation of spine head diameter in the hippocampus. These findings advance our understanding of neurotrophic function of brain sex steroids. Our method is expected to be valuable to analyze vast amounts of dendritic spines in neurons in the mammalian cerebral cortex.
Cerebral Cortex 04/2011; 21(12):2704-11. · 6.54 Impact Factor
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ABSTRACT: Neuroactive steroids are synthesized in the central and peripheral nervous systems. The purpose of this study was to analyze the effects of environmental enrichment on neuroactive steroidogenesis in the rat hippocampus. Environmental enrichment rats were housed in a group of nine in a large cage and three groups of pair-housed rats were housed in a standard cage for 8 weeks. The levels of mRNAs for steroidogenic enzymes and proteins in hippocampus were quantified by real-time RT-PCR. Environmental enrichment increased the mRNA expression levels of 5α-reductase-1 and 3α-hydroxysteroid dehydrogenase, which catalyze synthesis of allopregnanolone from progesterone. Hence, environmental enrichment appears to affect allopregnanolone synthesis.
General and Comparative Endocrinology 03/2011; 171(1):28-32. · 3.27 Impact Factor
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Yasushi Hojo,
Shimpei Higo, Suguru Kawato,
Yusuke Hatanaka,
Yuuki Ooishi,
Gen Murakami,
Hirotaka Ishii,
Yoshimasa Komatsuzaki,
Mari Ogiue-Ikeda,
Hideo Mukai,
Tetsuya Kimoto
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ABSTRACT: Sex steroids play essential roles in the modulation of synaptic plasticity and neuroprotection in the hippocampus. Accumulating evidence shows that hippocampal neurons synthesize both estrogen and androgen. Recently, we also revealed the hippocampal synthesis of corticosteroids. The accurate concentrations of these hippocampus-synthesized steroids are determined by liquid chromatography-tandem mass-spectrometry in combination with novel derivatization. The hippocampal levels of 17β-estradiol (E2), testosterone (T), dihydrotestosterone (DHT), and corticosterone (CORT), are 5-15 nM, and these levels are sufficient to modulate synaptic plasticity. Hippocampal E2 modulates memory-related synaptic plasticity not only slowly/genomically but also rapidly/non-genomically. Slow actions of E2 occur via classical nuclear receptors (ERα or ERβ), while rapid E2 actions occur via synapse-localized or extranuclear ERα or ERβ. Nanomolar concentrations of E2 change rapidly the density and morphology of spines in hippocampal neurons. ERα, but not ERβ, drives this enhancement/suppression of spinogenesis in adult animals. Nanomolar concentrations of androgens (T and DHT) and CORT also increase the spine density. Kinase networks are involved downstream of ERα and androgen receptor. Newly developed Spiso-3D mathematical analysis is useful to distinguish these complex effects by sex steroids and kinases. Significant advance has been achieved in investigations of rapid modulation by E2 of the long-term depression or the long-term potentiation.
Frontiers in endocrinology. 01/2011; 2:43.
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Shimpei Higo,
Yasushi Hojo,
Hirotaka Ishii,
Yoshimasa Komatsuzaki,
Yuuki Ooishi,
Gen Murakami,
Hideo Mukai,
Takeshi Yamazaki,
Daiichiro Nakahara,
Anna Barron,
Tetsuya Kimoto, Suguru Kawato
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ABSTRACT: Brain synthesis of steroids including sex-steroids is attracting much attention. The endogenous synthesis of corticosteroids in the hippocampus, however, has been doubted because of the inability to detect deoxycorticosterone (DOC) synthase, cytochrome P450(c21).
The expression of P450(c21) was demonstrated using mRNA analysis and immmunogold electron microscopic analysis in the adult male rat hippocampus. DOC production from progesterone (PROG) was demonstrated by metabolism analysis of (3)H-steroids. All the enzymes required for corticosteroid synthesis including P450(c21), P450(2D4), P450(11β1) and 3β-hydroxysteroid dehydrogenase (3β-HSD) were localized in the hippocampal principal neurons as shown via in situ hybridization and immunoelectron microscopic analysis. Accurate corticosteroid concentrations in rat hippocampus were determined by liquid chromatography-tandem mass spectrometry. In adrenalectomized rats, net hippocampus-synthesized corticosterone (CORT) and DOC were determined to 6.9 and 5.8 nM, respectively. Enhanced spinogenesis was observed in the hippocampus following application of low nanomolar (10 nM) doses of CORT for 1 h.
These results imply the complete pathway of corticosteroid synthesis of 'pregnenolone →PROG→DOC→CORT' in the hippocampal neurons. Both P450(c21) and P450(2D4) can catalyze conversion of PROG to DOC. The low nanomolar level of CORT synthesized in hippocampal neurons may play a role in modulation of synaptic plasticity, in contrast to the stress effects by micromolar CORT from adrenal glands.
PLoS ONE 01/2011; 6(7):e21631. · 4.09 Impact Factor
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ABSTRACT: Although sex steroids play a crucial role in the postnatal brain development, the age-related changes in the hippocampal steroidogenesis remain largely unknown. We performed comprehensive investigations for the mRNA expressions of 26 sex steroidogenic enzymes/proteins and three sex steroid receptors in the male rat hippocampus, at the ages of postnatal day (PD) 1, PD4, PD7, PD10, PD14, 4 wk, and 12 wk (adult), by RT-PCR/Southern blotting analysis. The relative expression levels of these enzymes/receptors at PD1 were Srd5a1 > Star > Ar ∼ Hsd17b4 ∼ Hsd17b1 ∼ Hsd17b7 ∼ Esr1 ∼ Srd5a2 > Hsd17b3 > Esr2 > Cyp11a1 > Cyp17a1 > Cyp19a1 ∼ Hsd17b2 > 3β-hydroxysteroid dehydrogenase I. The mRNA levels of essential enzymes for progesterone/testosterone/estradiol metabolisms (Cyp17a1, Hsd17b7, and Cyp19a1) were approximately constant between PD1 and PD14 and then declined toward the adult levels. Cyp11a1 increased during PD4-PD14 and then considerably decreased toward the adult level (∼8% of PD1). Hsd17b1, Hsd17b2, and 3β-hydroxysteroid dehydrogenase I mRNA decreased approximately monotonously. Hsd17b3 increased to approximately 200% of PD1 during PD4-PD14 and was maintained at this high level. The 5α-reductase mRNA was maintained constant (Srd5a1) or decreased monotonically (Srd5a2) toward the adult level. The Esr1 level peaked at PD4 and decreased toward the adult level, whereas Ar greatly increased during PD1-PD14 and was maintained at this high level. The Star and Hsd17b4 levels were maintained constant from neonate to adult. These results suggest that the hippocampal sex steroidogenic properties are substantially altered during the postnatal development processes, which might contribute to brain sexual maturation.
Endocrinology 11/2010; 151(12):5795-806. · 4.46 Impact Factor
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ABSTRACT: The hippocampus is a center for learning and memory as well as a target of Alzheimer's disease in aged humans. Synaptic modulation by estrogen is essential to understand the molecular mechanisms of estrogen replacement therapy. Because the local synthesis of estrogen occurs in the hippocampus of both sexes, in addition to the estrogen supply from the gonads, its functions are attracting much attention. Hippocampal estrogen modulates memory-related synaptic plasticity not only slowly but also rapidly. Slow actions of 17ß-estradiol (17ß-E2) occur via classical nuclear receptors (ERα or ERß), while rapid E2 actions occur via synapse-localized ERα or ERß. Elevation or decrease of the E2 concentration changes rapidly the density and morphology of spines in CA1-CA3 neurons. ERα, but not ERß, drives this enhancement/suppression of spinogenesis. Kinase networks are involved downstream of ERα. The long-term depression but not the long-term potentiation is modulated rapidly by changes of E2 level. Determination of the E2 concentration in the hippocampus is enabled by mass-spectrometry in combination with derivatization methods. The E2 level in the hippocampus is as high as approx. 8 nM for the male and 0.5-2 nM for the female, which is much higher than that in circulation. Therefore, hippocampus-derived E2 plays a major role in modulation of synaptic plasticity. Many hippocampal slice experiments measure the restorative effects of E2 by supplementation of E2 to E2-depleted slices. Accordingly, isolated slice experiments can be used as in vitro models of in vivo estrogen replacement therapy for ovariectomized female animals with depleted circulating estrogen.
Biochimica et Biophysica Acta 11/2009; 1800(10):1030-44. · 4.66 Impact Factor
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Yasushi Hojo,
Shimpei Higo,
Hirotaka Ishii,
Yuuki Ooishi,
Hideo Mukai,
Gen Murakami,
Toshihiro Kominami,
Tetsuya Kimoto,
Seijiro Honma,
Donald Poirier, Suguru Kawato
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ABSTRACT: Estradiol (E2) and other sex steroids play essential roles in the modulation of synaptic plasticity and neuroprotection in the hippocampus. To clarify the mechanisms for these events, it is important to determine the respective role of circulating vs. locally produced sex steroids in the male hippocampus. Liquid chromatography-tandem mass spectrometry in combination with novel derivatization was employed to determine the concentration of sex steroids in adult male rat hippocampus. The hippocampal levels of 17beta-E2, testosterone (T), and dihydrotestosterone (DHT) were 8.4, 16.9, and 6.6 nm, respectively, and these levels were significantly higher than circulating levels. The hippocampal estrone (E1) level was, in contrast, very low around 0.015 nm. After castration to deplete circulating high level T, hippocampal levels of T and DHT decreased considerably to 18 and 3%, respectively, whereas E2 level only slightly decreased to 83%. The strong reduction in hippocampal DHT resulting from castration implies that circulating T may be a main origin of DHT. In combination with results obtained from metabolism analysis of [(3)H]steroids, we suggest that male hippocampal E2 synthesis pathway may be androstenedione --> T --> E2 or dehydroepiandrosterone --> androstenediol --> T --> E2 but not androstenedione --> E1 --> E2.
Endocrinology 07/2009; 150(11):5106-12. · 4.46 Impact Factor
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ABSTRACT: Glucocorticoids are known to decrease intracellular ATP levels in the brain. This study was performed to investigate whether corticosterone at physiological levels depresses mitochondrial ATP production by directly acting on mitochondria. Mitochondria were isolated from immortalized hypothalamic GT1-7 neurons. ATP levels were determined using a luciferase-luciferin assay. When malate, alpha-ketoglutarate or pyruvate was used as a respiration substrate, corticosterone at > or =100 nM decreased ATP production by 10%. In contrast, corticosterone did not affect ATP production when succinate or N,N,N',N'-tetramethyl-p-phenylenediamine+ascorbate were used. To investigate the specificity of corticosterone inhibition, we examined several steroids. All steroids tested suppressed mitochondrial ATP production by 10% at a concentration of 100 nM, in a manner similar to that of corticosterone. To examine the effects of corticosterone on GT1-7 cell physiology, we incubated GT1-7 cells with t-butyl hydroperoxide (t-BuOOH) with corticosterone. Corticosterone largely enhanced t-BuOOH-induced cell death. These results indicate that corticosterone non-specifically inhibits mitochondrial ATP production by suppressing electron transfer from NADH to the electron transfer chain through complex I. Partial inhibition of mitochondrial ATP production by corticosterone may contribute to oxidative stress-induced cell death.
The Journal of steroid biochemistry and molecular biology 07/2009; 117(1-3):50-5. · 2.66 Impact Factor
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ABSTRACT: The hippocampus is essentially involved in learning and memory processes. Its functions are affected by various neuromodulators, including 17beta-estradiol, testosterone, and retinoid. Brain-synthesized steroid hormones act as autocrine and paracrine modulators. The regulatory mechanism underlying brain steroidogenesis has not been fully elucidated. Synthesis of sex steroids in the gonads is stimulated by retinoic acids. Therefore, we examined the effects of retinoic acids on estradiol and testosterone biosynthesis in the rat hippocampus. We used cultured hippocampal slices from 10- to 12-d-old male rats to investigate de novo steroidogenesis. The infant rat hippocampus possesses mRNAs for steroidogenic enzymes and retinoid receptors. Slices were used after 24 h of preculture to obtain maximal steroidogenic activity because steroidogenesis in cultured slices decreases with time. The mRNA levels for P450(17alpha), P450 aromatase and estrogen receptor-beta in the slices were increased by treatment with 9-cis-retinoic acid but not by all-trans-isomer. The magnitude of stimulation and the shape of the dose-response curve for the mRNA level for P450(17alpha) were similar to those for cellular retinoid binding protein type 2, the transcription of which is activated by retinoid X receptor signaling. 9-cis-Retinoic acid also induced a 1.7-fold increase in the protein content of P450(17alpha) and a 2-fold increase in de novo synthesis of 17beta-estradiol and testosterone. These steroids may be synthesized from a steroid precursor(s), such as pregnenolone or other steroids, or from cholesterol, as so-called neurosteroids. The stimulation of estradiol and testosterone synthesis by 9-cis-retinoic acid might be caused by activation of P450(17alpha) transcription via retinoid X receptor signaling.
Endocrinology 07/2009; 150(9):4260-9. · 4.46 Impact Factor
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ABSTRACT: Sex-steroid synthesis in the hippocampus had been thought to be much more active at the neonatal stage than at the adult stage. However, the detailed comparison between these two stages had not been demonstrated yet. Here we performed the comparison about the mRNA level of steroidogenic enzymes and the rate of steroid metabolism between these two stages of the hippocampus. The relative expression level of P450(17alpha), 17beta- or 3beta-hydroxysteroid dehydrogenase, or P450arom was approximately 1.3-1.5-fold higher at the neonatal than at the adult stage. The rate of sex-steroid metabolism (from dehydroepiandrosterone to estradiol) was 2-7-fold (depending on different steps) more rapid at the neonatal than at the adult stage. Taken together, neonatal steroidogenesis is moderately more active than adult steroidogenesis.
Biochemical and Biophysical Research Communications 06/2009; 385(1):62-6. · 2.48 Impact Factor
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ABSTRACT: Imaging of trafficking of endosomes containing low-density lipoprotein (LDL) is useful to analyze cholesterol transport in adrenocortical cells. At 60 min after the application of fluorescently labeled LDL to adrenocortical cells, individual endosomes containing LDL were demonstrated to undergo frequent switching between forward and reverse movement and immobility. The population of moving endosomes (>or=0.065 microm/s) was approximately 75% in control cells. The remaining endosomes were either slowly moving or temporarily immobile. At 3h after the LDL addition, endosomes were concentrated around the circumference of the cell nuclei. The endosome movement was inhibited by nocodazole, implying that endosomes undergo movement along microtubule networks. Anti-dynein antibodies inhibited the motion of endosomes towards the nucleus, and anti-kinesin antibodies inhibited peripherally directed motion. These results imply that both dynein-like and kinesin-like motor proteins bind to the same endosome, resulting in saltatory movements with centripetal or peripherally directed direction, depending on which motor binds to microtubules. Though the dynein and kinesin motors drive the endosomes very rapidly (microm/s), frequent saltatory motions of single endosomes may induce the very slow net centripetal motion (microm/h).The application of adrenocorticotropic hormone (ACTH) resulted in a facilitation of the centripetal motion of endosomes, resulting in the establishment of the concentration of endosomes around cell nuclei within 1 h.
Molecular and Cellular Endocrinology 05/2009; 307(1-2):185-95. · 4.19 Impact Factor
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ABSTRACT: Modulation of hippocampal synaptic plasticity by androgen has been attracting much attention. Thorns of thorny excrescences of CA3 hippocampal neurons are post-synaptic regions whose presynaptic partners are mossy fiber terminals. Here we demonstrated rapid effects of dihydrotestosterone (DHT) and testosterone (T) on the density of thorns, by imaging Lucifer Yellow-injected neurons in adult male rat hippocampal slices. The application of 10nM DHT or T induced rapid increase in the density of thorns within 2h. The androgen-mediated increase was suppressed by blocking several kinases, such as Erk MAPK, p38 MAPK, PKC, and CaMKII. On the other hand, PKA, PI3K were not involved in the signaling of thorn-genesis. The increase in the thorn density by androgen was also blocked by the inhibitor of classical androgen receptor. Almost no difference was observed between DHT and T in the effect on the thorn density. We observed that the androgen-induced thorn-genesis is opposite to estrogen-induced thorn-degeneration.
Biochemical and Biophysical Research Communications 05/2009; 381(4):728-32. · 2.48 Impact Factor
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ABSTRACT: 17beta-estradiol is synthesized de novo in the rat hippocampus. However, the regulatory mechanism of hippocampal estradiol synthesis has remained unclear. We investigated the effects of social isolation on rat hippocampal estradiol synthesis. Rats were divided into two groups: social isolation and pair housed group. Socially isolated rats were housed individually while pair housed rats were housed two per cage for 8 weeks. Social isolation activated the transcription of neurosteroidogenic molecules, including steroidogenic acute regulatory protein (StAR) and CYP19 (cytochrome P450arom). These two molecules are involved in the regulatory step for steroidogenesis and final step of estradiol synthesis. In contrast, the mRNA levels were not affected in rat olfactory bulb. The hippocampal estradiol content was increased in accordance with the increased mRNA levels. The hippocampal estradiol content exhibited correlations with the StAR and P450arom mRNA levels. These data suggest that social isolation may enhance de novo estradiol synthesis in the hippocampus.
Biochemical and Biophysical Research Communications 01/2009; 379(2):480-4. · 2.48 Impact Factor
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ABSTRACT: 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.
Molecular and Cellular Endocrinology 06/2008; 290(1-2):31-43. · 4.19 Impact Factor
