Biosynthesis, Mode of Action, and Functional Significance of Neurosteroids in the Purkinje Cell

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.

Levels and actions of progesterone and its metabolites in the nervous system during physiological and pathological conditions

“…PROG has also developmental effects in the brain, regulating the development of some neuronal types, such as the Purkinje cells of the cerebellum (Tsutsui et al, 2011). Another important developmental action of PROG is the regulation of the differentiation and proliferation of oligodendrocytes (Ghoumari et al, 2003(Ghoumari et al, , 2005Jung-Testas et al, 1996b).…”

Acute inhibition of estradiol synthesis impacts vestibulo-ocular reflex adaptation and cerebellar long-term potentiation in male rats

“…So far, evidence indicates that the cerebellum expresses estrogen receptors (α, β, GPER) and can produce key enzymes for E2 formation (Hazell et al 2009;Hedges et al 2012;Sakamoto et al 2003;Tsutsui et al 2011). Moreover, an effect of chronic E2 administration in ovariectomized mice on Purkinje cell (PC) plasticity and on VOR adaptation has been shown (Andreescu et al 2007).…”

Programming the Brain and Behaviour by Early‐Life Stress: A Focus on Neuroactive Steroids

“…Neuroactive steroids (endogenous steroids that exert rapid nongenomic effects on neuronal excitability) play a significant role in neurodevelopment in terms of neuroprotection and neuronal organisation: they promote neuronal survival and differentiation, myelinisation, dendritic growth and synaptogenesis (6)(7)(8). Hence, it is perhaps unsurprising that several neurodevelopmental disorders, mood disorders and cognitive decline have been associated with a perturbation in neurosteroid levels (9)(10)(11)(12)(13)(14)(15)(16).…”