Endogenous Synthesis of Corticosteroids in the Hippocampus

Abstract

BackgroundBrain 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 FindingsThe 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(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.Conclusions/SignificanceThese 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.

Accurate determination of tissue steroid hormones, precursors and conjugates in adult male rat

“…However, 11b-hydroxylase catalyses the conversion of 11-DCC to CCS, and we found a significant level of 11-DCC in the testis (Table II), indicating the possibility of the biosynthesis of CCS via the 11b-hydroxylation of the 11-DCC detected in rat testis. We also observed significant levels of 11-DCC in the brain, suggesting the possibility of CCS biosynthesis in the brain, as previously reported in the hippocampus (33). Recently, neurosteroid glucuronides have been found in mouse brain by LC-MS analysis, and the authors showed the formation of those glucuronides in vitro using a brain homogenate S-9 fraction (34).…”

Modulation of synaptic plasticity in the hippocampus by hippocampus-derived estrogen and androgen

“…Note that synaptically localized GR, ER␣ were observed by immunoelectron microscopic analysis (Fig. 6) [16,25]. Under these conditions of weakend LTP by CORT, ER␣ may play significant role due to lower Ca 2+ concentration (may be 5 M).…”

Hippocampal spine changes across the sleep–wake cycle: corticosterone and kinases

“…We have found that even 10 nM CORT is enough to increase the spine density ( Supplementary Fig. S9, see section on supplementary data given at the end of this article; Higo et al 2011).…”

“…The average concentration of CORT in the hippocampus was 23.7 ng/g wet weight (68.4 nM; nZ3), slightly higher than that in the CSF of intact rats in the awake state (w30 nM). Upon CORT injection into ADX rats, the hippocampal CORT became much higher than that in ADX rats without CORT injection (6.9 nM; Higo et al 2011).…”