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      Local Neurosteroid Production in the Hippocampus: Influence on Synaptic Plasticity of Memory

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          In neuroendocrinology, it is believed that steroid hormones are synthesized in the gonads and/or adrenal glands, and reach the brain via the blood circulation. In contrast to this view, we are in progress of demonstrating that estrogens and androgens are also synthesized locally by cytochrome P450s in the hippocampus, and that these steroids act rapidly to modulate neuronal synaptic plasticity. We demonstrated that estrogens were locally synthesized in the adult hippocampal neurons. In the pathway of steroidogenesis, cholesterol is converted to pregnenolone (by P450scc), dehydroepiandrosterone [by P450(17α)], androstenediol (by 17β-hydroxysteroid dehydrogenase, 17β-HSD), testosterone (by 3β-HSD) and finally to estradiol (by P450arom) and dihydrotestosterone (by 5α-reductase). The basal concentration of estradiol in the hippocampus was approximately 1 n M, which was greater than that in blood plasma. Significant expression of mRNA for P450scc, P450(17α), P450arom, 17β-HSD, 3β-HSD and 5α-reductase was demonstrated by RT-PCR. Their mRNA levels in the hippocampus were 1/200–1/5,000 of those in the endocrine organs. Localization of P450(17α) and P450arom was observed in synapses in addition to endoplasmic reticulum of principal neurons using immunoelectron microscopy. Different from slow action of gonadal estradiol which reaches the brain via the blood circulation, hippocampal neuron-derived estradiol may act locally and rapidly within the neurons. For example, 1 n M 17β-estradiol rapidly enhanced the long-term depression (LTD) not only in CA1 but also in CA3 and dentate gyrus. The density of thin spines was selectively increased within 2 h upon application of 1 n M estradiol in CA1 pyramidal neurons. Only ERα agonist propyl-pyrazole-trinyl-phenol induced the same enhancing effect as estradiol on both LTD and spinogenesis in the CA1. ERβ agonist hydroxyphenyl-propionitrile suppressed LTD and did not affect spinogenesis. Localization of estrogen receptor ERα in spines in addition to nuclei of principal neurons implies that synaptic ERα can drive rapid modulation of synaptic plasticity by endogenous estradiol.

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          Most cited references 32

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          Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P450 aromatase localized in neurons.

          In adult mammalian brain, occurrence of the synthesis of estradiol from endogenous cholesterol has been doubted because of the inability to detect dehydroepiandrosterone synthase, P45017alpha. In adult male rat hippocampal formation, significant localization was demonstrated for both cytochromes P45017alpha and P450 aromatase, in pyramidal neurons in the CA1-CA3 regions, as well as in the granule cells in the dentate gyrus, by means of immunohistochemical staining of slices. Only a weak immunoreaction of these P450s was observed in astrocytes and oligodendrocytes. ImmunoGold electron microscopy revealed that P45017alpha and P450 aromatase were localized in pre- and postsynaptic compartments as well as in the endoplasmic reticulum in principal neurons. The expression of these cytochromes was further verified by using Western blot analysis and RT-PCR. Stimulation of hippocampal neurons with N-methyl-d-aspartate induced a significant net production of estradiol. Analysis of radioactive metabolites demonstrated the conversion from [(3)H]pregnenolone to [(3)H]estradiol through dehydroepiandrosterone and testosterone. This activity was abolished by the application of specific inhibitors of cytochrome P450s. Interestingly, estradiol was not significantly converted to other steroid metabolites. Taken together with our previous finding of a P450scc-containing neuronal system for pregnenolone synthesis, these results imply that 17beta-estradiol is synthesized by P45017alpha and P450 aromatase localized in hippocampal neurons from endogenous cholesterol. This synthesis may be regulated by a glutamate-mediated synaptic communication that evokes Ca(2+) signals.
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            NMDA induces long-term synaptic depression and dephosphorylation of the GluR1 subunit of AMPA receptors in hippocampus.

            Brief bath application of N-methyl-D-aspartate (NMDA) to hippocampal slices produces long-term synaptic depression (LTD) in CA1 that is (1) sensitive to postnatal age, (2) saturable, (3) induced postsynaptically, (4) reversible, and (5) not associated with a change in paired pulse facilitation. Chemically induced LTD (Chem-LTD) and homosynaptic LTD are mutually occluding, suggesting a common expression mechanism. Using phosphorylation site-specific antibodies, we found that induction of chem-LTD produces a persistent dephosphorylation of the GluR1 subunit of AMPA receptors at serine 845, a cAMP-dependent protein kinase (PKA) substrate, but not at serine 831, a substrate of protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII). These results suggest that dephosphorylation of AMPA receptors is an expression mechanism for LTD and indicate an unexpected role of PKA in the postsynaptic modulation of excitatory synaptic transmission.
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              Characterization and measurement of dehydroepiandrosterone sulfate in rat brain.

              Dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one, I) sulfate (Ia) has been characterized in the anterior and the posterior parts of the brain of adult male rats. Its level (1.58 +/- 0.14 and 4.89 +/- 1.06 ng/g, mean +/- SD, in anterior and posterior brain, respectively) largely exceeded that of I in brain (0.42 +/- 0.10 and 0.12 +/- 0.03 ng/g in anterior and posterior brain, respectively) and of Ia in plasma (0.26 +/- 0.13 ng/ml). Brain Ia level did not seem to depend on adrenal secretion; it was unchanged after administration of corticotropin or dexamethasone for 3 days, and no meaningful change occurred in brain 15 days after adrenalectomy plus orchiectomy, compared with sham-operated controls. In contrast, stress conditions prevailing 2 days after adrenalectomy plus orchiectomy or after the corresponding sham operation resulted in a significantly increased concentration of Ia in the brain. Changes of Ia level in brain occurred irrespective of changes in corresponding plasma samples. It is proposed that Ia formation or accumulation (or both) in the rat brain depends on in situ mechanisms unrelated to the peripheral endocrine gland system.

                Author and article information

                S. Karger AG
                February 2007
                05 March 2007
                : 84
                : 4
                : 255-263
                aDepartment of Biophysics and Life Sciences, bCore Research for Evolutional Science and Technology Project of Japan Science and Technology Agency, cProject of Special Coordinate Funds for Promoting Science and Technology, and dBioinformatics Project of Japan Science and Technology Agency, Graduate School of Arts and Sciences, The University of Tokyo, Komaba, Meguro, Tokyo, Japan
                97747 Neuroendocrinology 2006;84:255–263
                © 2006 S. Karger AG, Basel

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                Page count
                Figures: 4, Tables: 1, References: 52, Pages: 9
                Neurosteroids and Neuroprotection


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