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Role of Cytochrome P450 in Synaptocrinology: Endogenous Estrogen Synthesis in the Brain Hippocampus

In the hippocampus, the center for learning and memory, cytochrome P450s (P450scc, P450(17α), and P450arom) as well as 17β-, 3β-hydroxysteroid dehydrogenases, and 5α-reductase participate in the synthesis of brain steroids from endogenous cholesterol. These brain steroids include pregnenolone, dehydroepiandrosterone, testosterone, dihydrotestosterone, and 17β-estradiol. Both estrogens and androgens are synthesized in the adult male hippocampal neurons. Although the expression levels of steroidogenic enzymes are as low as 1/200 to 1/50,000 of those in testis or ovary, the levels of synthesized steroids are sufficient for the local usage within small neurons (i.e., intracrine system). This intracrine system contrasts with the endocrine system in which high expression levels of steroidogenic enzymes are necessary in endocrine organs in order to supply steroids to many other organs via blood circulation. Endogenous synthesis of sex steroids in the hypothalamus is also discussed. Rapid modulation by estrogens and xenoestrogens is discussed concerning synaptic plasticity such as the long-term potentiation, the long-term depression, or spinogenesis. Synaptic expression of P450(17α), P450arom, and estrogen receptors suggests “synaptocrine” mechanisms of brain steroids, which are synthesized at synapses and act as synaptic modulators.