Endogenous Synthesis of Corticosteroids in the Hippocampus

Higo Shimpei

Hojo Yasushi

Ishii Hirotaka

Komatsuzaki Yoshimasa

Ooishi Yuuki

Murakami Gen

Mukai Hideo

Yamazaki Takeshi

Nakahara Daiichiro

Barron Anna

Kimoto Tetsuya

Kawato Suguru

PLoS ONE

Background: 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).

Methodology/Principal Findings: 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 3H-steroids. All the enzymes required for corticosteroid synthesis including P450(c21), P450(2D4), P450(11b1) and 3b-hydroxysteroid dehydrogenase (3b-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.

Conclusions/Significance: These results imply the complete pathway of corticosteroid synthesis of ‘pregnenolone RPROGRDOCRCORT' 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.

Medical sciences [ 490 ]

eng

Public Library of Science

(c) 2011 Higo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

[ISSN] 1932-6203

[DOI] 10.1371/journal.pone.0021631

[DOI] http://dx.doi.org/10.1371/journal.pone.0021631