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.
Highlights
Estrogens are part of the neuroactive steroid family that may regulate the structure and function of neural networks via multiple modes and time courses
The estradiol impacts on neural physiology depend on its bioavailability in a brain structure, and it has been shown that, in addition to peripheral synthesis such as in the gonads, the estradiol can be locally produced in the nervous system [8]
The production of nE2 requires an aromatase-dependent conversion of testosterone, which may be either of the peripheral origins or locally synthesized from the precursor cholesterol [9,10,11,12]
Summary
Estrogens are part of the neuroactive steroid family that may regulate the structure and function of neural networks via multiple modes and time courses. Faster non-classical and often membrane-initiated mechanisms are observable within a few seconds (for some electrophysiological effects) to minutes after estradiol activated signaling involving intracellular cascades that may include several protein kinases and result in cytoplasmatic fluctuations of calcium concentration (Figure 2) [19,20,21,22,23,24]. Some of these intracellular signalings could affect the gene transcription through the so-called “indirect genetic. It is reasonable to assume that a role of nE2 in controlling neuronal functioning via modulation of synaptic transmission, similar to that detected in the cerebellum, could be extended to other brain regions where so far, due to low aromatase expression, estradiol synthesis has been not identified or considered not functionally relevant
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