Abstract
The brain has traditionally been considered to be a target site of peripheral steroid hormones. In addition to this classical concept, we now know that the brain has the capacity to synthesize steroids de novo from cholesterol, the so-called “neurosteroids.” In the middle 1990s, the Purkinje cell, an important cerebellar neuron, was identified as a major site for neurosteroid formation in the brain of mammals and other vertebrates. This discovery has provided the opportunity to understand neuronal neurosteroidogenesis in the brain. In addition, biological actions of neurosteroids are becoming clear by the studies using the Purkinje cell, an excellent cellular model, which is known to play an important role in memory and learning processes. Based on the studies on mammals over the past decade, it is considered that the Purkinje cell actively synthesizes progesterone and estradiol 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 mediated by neurotrophic factors may contribute to the formation of cerebellar neuronal circuit during neonatal life. 3α,5α-Tetrahydroprogesterone (allopregnanolone), a progesterone metabolite, is also synthesized in the cerebellum and considered to act as a survival factor of Purkinje cells in the neonate. This review summarizes the current knowledge regarding the biosynthesis, mode of action, and functional significance of neurosteroids in the Purkinje cell during development in terms of synaptic formation of cerebellar neuronal networks.
Highlights
The cerebellar cortex forms relatively simple neuronal networks compared to those of other brain regions
In addition to higher vertebrates, Tsutsui and colleagues further identified P450 side-chain cleavage (P450scc) in the Purkinje cell of amphibians (Takase et al, 1999). These findings indicate that Purkinje cells possess P450scc and produce pregnenolone in vertebrates (Figure 1)
The NT-3 level did not change in ArKO mice as well (Sasahara et al, 2007). These results indicate that brain-derived neurotrophic factor (BDNF) mediates estrogen action on the promotion of dendritic growth, spinogenesis, and synaptogenesis in the Purkinje cell during neonatal development (Figure 3)
Summary
The cerebellar cortex forms relatively simple neuronal networks compared to those of other brain regions. In the middle 1990s, Tsutsui and colleagues discovered that the Purkinje cell, an important cerebellar neuron, is a major site for neurosteroid formation in a variety of vertebrates including mammals (Tsutsui and Yamazaki, 1995; Usui et al, 1995; Ukena et al, 1998, 1999; Takase et al, 1999; Matsunaga et al, 2001; Sakamoto et al, 2001a, 2003a; Agís-Balboa et al, 2006, 2007) This was the first observation of neuronal neurosteroidogenesis in the brain. Frontiers in Endocrinology | Neuroendocrine Science essential role in the process of memory and learning This neuron expresses a key enzyme of estrogen formation, cytochrome P450 aromatase (P450arom), and actively produces estradiol in the neonate (Sakamoto et al, 2003a; Tsutsui et al, 2003b; Figure 1). Estradiol may contribute to important events in the developing Purkinje cell (Sakamoto et al, 2003a; Sasahara et al, 2007)
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