Recent evidence indicates that, besides their hormonal actions at the genetic level, estrogens such as 17 beta-estradiol also influence brain function by direct effects on neuronal membranes.
Anatomical localization of the estrogen synthesis enzyme (aromatase) within presynaptic terminals suggests that neuroestrogens can be synthesized directly at the neuronal synapse. A consequent prediction follows that synaptic estrogen production is controlled via classical electrochemical events in neurons. Classical neurotransmitter and neuropeptide release is dependent on depolarization-induced opening of presynaptic voltage-gated Ca2+ channels (VGCCs).
Estrogens can alter neuronal excitability within seconds to minutes in the amygdala, hippocampus, striatum, hindbrain, and cortex. Thus, brain-derived estrogens are increasingly considered genuine neuromodulators. It is unclear, however whether neuroestrogen production is controlled via electrochemical events that are the hallmark of neurotransmitter-based cell-to-cell communication.
In this study, Luke Remage-Healey and colleagues from the University of California Los Angeles (UCLA) provide evidence that estrogens are produced in the brain’s nerve cell terminals on demand and that estradiol may acts remarkably like a classic neurotransmitter.
The authors found that acute fluctuations in local neuroestrogen levels in the forebrain of the zebra finch depend on calcium influx within presynaptic terminals.
Generally, the study presents direct evidence that neuroestrogen fluctuations are dependent on summed (30 min) electrochemical events within presynaptic terminals in the zebra finch NCM. Thus, these findings are important for two reasons.
First, the neuroestrogen flux is under the control of classical depolarization-dependent phenomena, consistent with the hypothesis that neuroestrogens can fluctuate and modulate cortical information flow at a relatively fast time scale (i.e., ≤30 min). Second, results with the VGCC blocker ω-conotoxin are consistent with the hypothesis that the electrochemical control of neuroestrogens depends on Ca2+-dependent events localized to the neuronal synapse.
Accumulating physiological evidence has demonstrated that changes in neuronal synthesis of E2 and/or changes in brain aromatase activity can occur within minutes of stimulation. Glutamatergic agonists rapidly alter aromatase activity in the hypothalamus and E2 production in the hippocampus and in vivo microdialysis reveals that E2 production in the auditory forebrain is acutely glutamate-sensitive. This indicates that E2 is synthesized locally and changes rapidly in discrete brain nuclei.
The present study now extends these findings by directly revealing a candidate electrochemical mechanism for presynaptic control of brain E2 levels.
According to the authors, the working model for rapid neuroestrogen synthesis is as follows: (1) neuronal aromatase is expressed and biochemically active in presynaptic terminals; (2) brain aromatase activity and estradiol production are controlled by excitatory inputs, including glutamatergic activation; (3) neuronal estrogen production can be controlled by an excitatory, VGCC-dependent mechanism within presynaptic terminals (the present study); (4) extranuclear estrogen receptors occur in both presynaptic boutons and in dendritic processes indicative of a perisynaptic modulatory capacity.
The authors discuss that these findings begin to characterize a fundamental mechanism for rapid, presynaptic estrogen provisioning within neural circuits, and the role of the aromatase-positive fibers and boutons that are found throughout the CNS of vertebrates.
A 2018 excellent review by Juan Pablo Del Río and colleagues discuss the effects of sex hormones in the brain, where they also have an effect on different neurotransmitters such as GABA, serotonin, dopamine, and glutamate.
Steroid hormones with activity in the nervous system are called “neurosteroids” or “neuroactive steroids”. They may be synthesized de novo in the central and peripheral nervous systems by neurons and glial cells or, peripherally and then cross the blood-brain barrier.
Figure 1. Schematic view of (A) estradiol signaling in neural cells through both classical and non-classical pathways. In the classical signaling pathway (right) the steroid hormone binds to its receptor located in the cytoplasm; the activated receptor dimerizes and makes its way into the nucleus where it interacts with responsive elements to activate or inhibit gene transcription. In the non-classical pathway (left) steroid hormones act through membrane receptors, including the classical receptors, GPCR receptors, ionotropic receptors, tyrosine kinase receptors, and other neurotransmitter receptors. This non-classical pathway initiates cytosolic signaling cascades, modulating the activation of various proteins and of second messenger systems.
From “Steroid hormones and their action in women’s brains: the importance of hormonal balance“, by Juan Pablo Del Río, María I Alliende, Natalia Molina, Felipe G Serrano, Santiago Molina, Pilar Vigil, Frontiers in Public Health 6. 2018.
In the classical estrogenic pathway, estrogens diffuse into target cells activating estrogen receptors (ER) α and β which form dimers. The activated receptors go into the nucleus, where they bind to estrogen responsive elements (ERE) of DNA.The activation of the EREs results in gene transcription at the nuclear and mitochondrial levels.
In the non-classical pathway, estrogens act through different receptors (ERα, ERβ, GPER, and GqmER) located in the plasma membrane. Through these receptors, estrogen triggers the activation of different signaling cascades such as phosphatidylinositol-3-kinase (PI3K), phospholipase C (PLC), and mitogen-activated protein kinases (MAPK), second messengers, ion influx, and efflux. Finally, genomic transcription can also be induced by the non-classical pathway.
Utilizing both classical and non-classical pathways, neurosteroids participate in the physiological regulation of neurogenesis, neuronal survival, synaptic function, and myelin formation, thus influencing neuronal plasticity. Because of these effects, neurosteroids will have different modulatory actions, exerting control over mood, cognition, and behavior. Additionally, they have a neuroprotective role in relation to certain neurocognitive pathologies.