Hippocampal cytochrome P450s synthesize brain neurosteroids which are paracrine neuromodulators of synaptic signal transduction

Shibuya, Keisuke; Takata, Norio; Hojo, Yasushi; Furukawa, Aizo; Yasumatsu, Nobuaki; Kimoto, Tsunenobu; Enami, Taihei; Suzuki, Kumiko; Tanabe, Nari; Ishii, Hirotaka; Mukai, Hideo; Takahashi, Takehiro; Hattori, Takaaki; Kawato, Suguru

doi:10.1016/s0304-4165(02)00489-0

Cited by 126 publications

(76 citation statements)

References 90 publications

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“…In our previous work, the steroid synthesis was triggered by exposing neurons to NMDA, which induced a Ca 2ϩ influx through the NMDA receptors and resulted in the significant production of PREG(s) (5,7). A pool of full-length (37-kDa) steroidogenic acute regulatory protein (StAR) was processed to the truncated 30-kDa StAR upon NMDA stimulation (7).…”

Section: Discussionmentioning

confidence: 99%

“…Our elucidation of the estradiol-synthesis in principal neurons, which begins with cholesterol, introduces an essentially a new supply of brain neurosteroids, in addition to gonads. Estradiol synthesis may be dependent on NMDA receptor-mediated Ca 2ϩ influx, thereby dependent on synaptic communication (5,7). The concentration of endogenously synthesized estradiol by NMDA stimulation (Ϸ0.75 nM; see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…As both estradiol and testosterone may reach the brain via blood circulation, and extensive studies have been performed to investigate their role in modulating hippocampal plasticity and function (1)(2)(3)(4). Evidence is emerging that estrogen exerts not only the chronic/genomic effects but also a rapid/nongenomic influence on hippocampal synaptic plasticity (2,5). In addition to endocrine-derived hormones, recent experiments have demonstrated that hippocampal neurons may also be exposed to locally synthesized brain neurosteroids, such as pregnenolone (PREG) and its sulfated ester (6)(7)(8)(9).…”

Section: Stimulation Of Hippocampal Neurons With N-methyl-d-aspartatementioning

confidence: 99%

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Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons

Hojo

Hattori

Enami

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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588

506

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In adult mammalian brain, occurrence of the synthesis of estradiol from endogenous cholesterol has been doubted because of the inability to detect dehydroepiandrosterone synthase, P45017␣. In adult male rat hippocampal formation, significant localization was demonstrated for both cytochromes P45017␣ 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 P45017␣ 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 17␤-estradiol is synthesized by P45017␣ 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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Stimulation Of Hippocampal Neurons With N-methyl-d-aspartatementioning

confidence: 99%

See 1 more Smart Citation

Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons

Hojo

Hattori

Enami

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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588

506

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“…In some studies, the enzyme was not detected in human (11,12), mouse (13), or rat (12) brain, although some groups have found the enzyme in rat (14,15) and in frog (16) brain. Other studies have reported a very low hydroxysteroid sulfotransferase activity in rat (17) and human (18) brain.…”

mentioning

confidence: 98%

Novel lipoidal derivatives of pregnenolone and dehydroepiandrosterone and absence of their sulfated counterparts in rodent brain

Lière

Pianos

Eychenne

et al. 2004

Journal of Lipid Research

110

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A new sample preparation method coupled to GC-MS analysis was developed and validated for quantification of sulfate esters of pregnenolone (PREG-S) and dehydroepiandrosterone (DHEA-S) in rat brain. Using a solid-phase extraction recycling protocol, the results show that little or no PREG-S and DHEA-S ( Ͻ 1 pmol/g) is present in rat and mouse brain. These data are in agreement with studies in which steroid sulfates were analyzed without deconjugation. We suggest that the discrepancies between analyses with and without deconjugation are caused by internal contamination of brain extract fractions, supposed to contain steroid sulfates, by lipoidal forms of PREG and DHEA (L-PREG and L-DHEA, respectively). These derivatives can be acylated very efficiently with heptafluorobutyric anhydride and triethylamine, and their levels in rodent brain ( ‫ف‬ 1 nmol/g) are much higher than those of their unconjugated counterparts. They are distinct from fatty acid esters, and preliminary data do not favor structures such as sulfolipids or sterol peroxides. Noncovalent interactions between steroids and proteolipidic elements, such as lipoproteins, could account for some experimental data. Given their abundance in rodent brain, the structural characterization and biological functions of L-PREG and L-DHEA in the central nervous system merit considerable attention. Four years ago, we developed and validated an analytical procedure for measuring trace amounts of neurosteroids in brain tissue by GC-MS (1). This method, which includes solid-phase extraction (SPE) and HPLC as fractionation and purification steps, is very suitable for quantifying simultaneously numerous neurosteroids in small individual regions of the central nervous system (CNS) (2) or peripheral nervous system (3) with high sensitivity and accuracy. Interest was primarily focused on pregnenolone (PREG), dehydroepiandrosterone (DHEA), and their sulfated conjugates (PREG-S and DHEA-S, respectively) and on progesterone (PROG) and allopregnanolone (3 ␣ -hydroxy-5 ␣ -pregnan-20-one).Neurosteroids are synthesized by glial cells and neurons from cholesterol or from blood-borne precursors (4). In particular, PREG-S and DHEA-S are known to be neuroactive, and their major effects are the modulation of several neuronal membrane receptors, such as ␥ -aminobutyric acid (5, 6), N -methyl-d -aspartate (7), and σ receptors, by affecting neuronal excitability and behavior (8, 9). Notably, a physiologic function of PREG-S was suggested by the positive correlation between PREG-S levels in the hippocampus of aged rats and their spatial memory performance (10). However, some studies do not favor the concept that PREG-S and DHEA-S are actually neurosteroids. Indeed, contradictory results have been obtained concerning the presence and activity of the hydroxysteroid sulfotransferase, implied in the sulfation of free steroid.

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“…Aromatase is the final enzyme of estradiol synthesis and catalyzes the conversion of testosterone to estradiol. It has meanwhile been established that the brain is equipped with all the enzymes of estrogen synthesis, including aromatase (Shibuya et al, 2003;Do Rego et al, 2009;Pelletier, 2010). The actual synthesis and secretion of estradiol from hippocampal neurons, however, was not shown until many years later (Prange-Kiel et al, 2003).…”

Section: Hippocampal Neurons Synthesize Estradiol Independent Of Gendermentioning

confidence: 99%

Sexual dimorphism in estrogen-induced synaptogenesis in the adult hippocampus

Brandt

Vierk²,

Rune³

2013

Int. J. Dev. Biol.

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It has long been known that estradiol influences synaptic plasticity in the female hippocampus. The density of dendritic spines varies during the estrous cycle and correlates positively with varying levels of estradiol in serum. In accordance, ovariectomy results in a loss of spines that can be rescued by estradiol treatment in animals, suggesting that estradiol originating from the ovaries induces spine formation in the hippocampus. More recent studies point to a role of hippocampusderived estradiol in synaptogenesis in the female hippocampus, rather than of estradiol of ovarian origin. In our studies, we have shown that inhibition of hippocampal estrogen synthesis results in spine synapse loss in female animals and, more importantly, also in ovariectomized animals. Surprisingly, inhibition of local estradiol synthesis had no effect on synapse formation in males, in spite of a similar capacity to synthesize estradiol in male and female hippocampal neurons. In females, neuro-sexual steroid production is promoted by hypothalamic, cyclic GnRH release and likely underlies the estrus cyclicity of spine synapse density in the hippocampus. As a result, peripheral serum concentrations of estradiol determine the amount of estradiol synthesis in the hippocampus. This paradigm may also be true in males. In support of this hypothesis, we found that the content of estradiol in hippocampal tissue is higher in female compared to that in male animals, with low levels of estradiol in serum and tonic and acyclical GnRH release. In summary, our data point to important sex-specific differences in sexual steroid-induced synaptogenesis.

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Hippocampal cytochrome P450s synthesize brain neurosteroids which are paracrine neuromodulators of synaptic signal transduction

Cited by 126 publications

References 90 publications

Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons

Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017α and P450 aromatase localized in neurons

Novel lipoidal derivatives of pregnenolone and dehydroepiandrosterone and absence of their sulfated counterparts in rodent brain

Sexual dimorphism in estrogen-induced synaptogenesis in the adult hippocampus

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