Progesterone biosynthesis and action in the developing neuron

The brain has traditionally been considered to be a target site of peripheral steroid hormones. By contrast, new findings over the past decade have shown that the brain itself also has the capability of forming steroids de novo, the so-called neurosteroids. De novo neurosteroidogenesis in the brain from cholesterol is a conserved property of vertebrates. When understanding the action of neurosteroids in the brain, data on the regio- and temporal-specific synthesis of neurosteroids are needed. Recently the Purkinje cell, an important brain neuron, has been identified as a major site for neurosteroid formation in vertebrates. This is the first demonstration of de novo neuronal neurosteroidogenesis in the brain. This discovery has allowed deeper insights into neuronal progesterone formation and organizing actions of progesterone have become clear by the studies using the Purkinje cell as an excellent cellular model, which is known to play an important role in memory and learning processes. In mammals, the Purkinje cell actively synthesizes progesterone de novo from cholesterol during neonatal life when cerebellar neuronal circuit formation occurs. Progesterone promotes dendritic growth, spinogenesis, and synaptogenesis via its nuclear receptor in the developing Purkinje cell. Such organizing actions may contribute to the formation of cerebellar neuronal circuit during neonatal life. Allopregnanolone, a progesterone metabolite, is also synthesized in the cerebellum and acts on Purkinje cell survival in the neonate. This paper summarizes the advances made in our understanding of progesterone formation and metabolism and actions of progesterone and its metabolite in the developing neuron.