The hippocampus is essentially involved in learning and memory processes. Its functions are affected by various neuromodulators, including 17-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 10–12-day-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 hours of pre-culture to obtain maximal steroidogenic activity, because steroidogenesis in cultured slices decreases with time.

The mRNA levels for P450₁₇, P450arom and estrogen receptor 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 P450₁₇ were similar to those for cellular retinoid binding protein type-2, 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 P450₁₇, and a 2-fold increase in de novo synthesis of 17-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 P450₁₇ transcription via retinoid X receptor signaling.