De Novo Synthesized Estradiol: A Role in Modulating the Cerebellar Function

Abstract

The estrogen estradiol is a potent neuroactive steroid that may regulate brain structure and function. Although the effects of estradiol have been historically associated with gonadal secretion, the discovery that this steroid may be synthesized within the brain has expanded this traditional concept. Indeed, it is accepted that de novo synthesized estradiol in the nervous system (nE2) may modulate several aspects of neuronal physiology, including synaptic transmission and plasticity, thereby influencing a variety of behaviors. These modulations may be on a time scale of minutes via non-classical and often membrane-initiated mechanisms or hours and days by classical actions on gene transcription. Besides the high level, recent investigations in the cerebellum indicate that even a low aromatase expression can be related to the fast nE2 effect on brain functioning. These pieces of evidence point to the importance of an on-demand and localized nE2 synthesis to rapidly contribute to regulating the synaptic transmission. This review is geared at exploring a new scenario for the impact of estradiol on brain processes as it emerges from the nE2 action on cerebellar neurotransmission and cerebellum-dependent learning.

Aromatase in the Human Brain

“…It will be also important to clarify the role of aromatase activity in the vestibular nuclei, the cerebellum, and the olivo-cerebellar system, 22 , 29 , 133 where estradiol locally produced by the enzyme may potentially be involved in the coordination or integration of sensory inputs with motor and cognitive processes. 134 A better understanding of the role of aromatase activity in the different regions of the human brain will contribute toward clarifying the controversial cognitive effects of aromatase inhibitors used as breast cancer therapies 135 , 136 and may also help to develop new treatments for specific brain pathological alterations based on drugs that modulate aromatase enzymatic activity or expression.…”

Steroid Sulfation in Neurodegenerative Diseases

“…Sex hormones are also active in the CNS. Particularly E2 exert pleiotropic effects there, facilitating learning and memory (Frick, 2015;Sun et al, 2019;Luine and Frankfurt, 2012;Tozzi et al, 2020;Dieni et al, 2020), as well as influencing emotional (Altemus, 2019) and sexual behavior (Diotel et al, 2018). They FIGURE 1 | Scheme of steroidogenesis.…”

“…Sex hormones are also active in the CNS. Particularly E2 exert pleiotropic effects there, facilitating learning and memory ( Frick, 2015 ; Sun et al, 2019 ; Luine and Frankfurt, 2012 ; Tozzi et al, 2020 ; Dieni et al, 2020 ), as well as influencing emotional ( Altemus, 2019 ) and sexual behavior ( Diotel et al, 2018 ). They generally act as neuroprotective substances ( Fargo et al, 2009 ; Spence and Voskuhl, 2012 ; Duong et al, 2020 ; Yang et al, 2020 ) and promote neurogenesis and neuro-regeneration ( Pillerová et al, 2021 ; Azcoitia et al, 2019 ).…”

On the role of sex steroids in biological functions by classical and non-classical pathways. An update

“…The E 2 can also modulate motor memory formation in the adult male CER ( Dieni et al, 2018 ). De novo synthesized E 2 modulates CER functions through cerebellar neurotransmission and CER-dependent learning ( Dieni et al, 2020 ). Furthermore, the improvement of cerebellar memory by E 2 is mediated through ERβ ( Andreescu et al, 2007 ).…”