Neurosteroid biosynthesis and action during cerebellar development.

The formation of the mammalian cerebellar cortex becomes complete in the neonate through the processes of migration of external granule cells, neuronal and glial growth, and synaptogenesis. In the middle 1990s, we identified the Purkinje cell, a principal cerebellar neuron, as a major site for neurosteroid formation in mammals. This discovery has provided the opportunity to understand neuronal neurosteroidogenesis and neurosteroid actions on neuronal growth and synaptic formation in the cerebellum. Based on extensive studies on mammals over the past decade, we now know that the Purkinje cell actively synthesizes progesterone and estradiol de novo from cholesterol during neonatal life, when cerebellar neuronal circuit formation occurs. Both progesterone and estradiol promote dendritic growth, spinogenesis, and synaptogenesis via each cognate nuclear receptor in the developing Purkinje cell. Such neurosteroid actions that may be mediated by neurotrophic factors 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 highlights the biosynthesis and biological actions of neurosteroids in the Purkinje cell during cerebellar development.