Neurosteroids and synaptic formation in the cerebellum

The cerebellar cortex has been used as an excellent model to study synaptic formation and transmission of neural networks because it forms relatively simple neuronal networks compared to those of other brain regions. 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. It is important to clarify the mechanism underlying synaptic formation of cerebellar neuronal networks during development. The brain has traditionally been considered to be a target site of peripheral steroid hormones. In contrast to this classical concept, new findings have shown that the brain has the capacity to synthesize steroids de novo from cholesterol, the so-called neurosteroids. In the middle 1990s, the Purkinje cell, a principal cerebellar neuron, was identified as a major site for neurosteroid formation in mammals as well as other vertebrates. This discovery has provided the opportunity to understand neuronal neurosteroidogenesis in the brain. In addition, biological actions of neurosteroids 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. Based on extensive studies on mammals over the past decade, it is considered 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 (3,5-tetrahydroprogesterone), a progesterone metabolite, is also synthesized in the cerebellum and acts on Purkinje cell survival in the neonate. This chapter summarizes the current knowledge regarding the biosynthesis and biological actions of neurosteroids in the cerebellum during development in terms of synaptic formation of cerebellar neuronal networks.