Summary: Researchers developed a highly selective fluorescent probe to image serotonin in cells and animal models, shedding light on its role in depression. The study revealed that while serotonin levels in normal and “depressed” cells are similar, depressive cells release significantly less serotonin.
The release ability correlates with the activity of mTOR, a biomolecule involved in cellular signaling. These findings suggest that serotonin release, not just its level, is critical in understanding and treating depression.
Key Facts:
- The fluorescent probe selectively detects serotonin, even inside cells.
- Depressed cells release less serotonin, correlating with mTOR activity.
- Findings could lead to new treatments focusing on serotonin release mechanisms.
Source: Wiley
Serotonin in depression is highly relevant in diagnosis, treatment, and drug development. To better study this area, a Chinese team has now developed a fluorescent probe for imaging processes that is highly sensitive and selective toward serotonin.
In the journal Angewandte Chemie, they also introduce the preliminary results obtained from the cell and animal models.
Depression represents a significant public health problem around the world. Current treatments are insufficient, primarily because it is difficult to determine the mechanism of depression. New studies indicate that depression is not exclusively caused by decreased serotonin levels.
To examine the role of serotonin in depression, a team led by Weiying Lin at Guangxi University (China) wanted to develop a highly selective molecular fluorescent probe. The problem with this is that serotonin’s structure and chemistry closely resemble other biomolecules, such as melatonin and tryptophan.
However, precise analyses have revealed subtle differences in reactivity. The team designed a special reactive group (3-mercaptopropionate) that can react very selectively with serotonin via a cascade reaction. They attached this reactive building block to a fluorescent dye (dicyanomethylene-benzopyran derivative).
Attachment of the “appendage” initially switches the probe “off”. If it encounters serotonin, one section reacts first (SH group of the reactive building block binds to a double bond in serotonin, thiol-ene click reaction). Afterward, facilitated by proximity, a second bond is formed (nucleophilic reaction between an amino group in serotonin and a carbonyl group in the reactive building block).
As a result, the building block is removed from the fluorescent dye and its fluorescence is switched “on”. The probe selectively and sensitively indicates the presence of serotonin, even inside cells.
The team used the probe to image a neuron cell line that can be made into a model for depression by the administration of corticosterone. It turned out that the serotonin level in the normal and “depressed” cells was nearly equally high.
However, the depressive cells were able to expel significantly less serotonin in response to stimulation. Administration of the current antidepressive drugs (serotonin reuptake inhibitors) slightly increased the release.
According to a hypothesis, mTOR, a biomolecule that plays a role in many cellular signaling pathways, could be related to a reduced ability to release serotonin. The team observed that with the mTOR activators, the serotonin release in the depressive cells was significantly increased, while the mTOR inhibitors reduce serotonin release from the normal cells. All results could be confirmed in the neuron and mouse models.
These imaging studies suggest that the serotonin level in the model for depression is not the primary factor. The ability of neurons to release serotonin seems far more critical. This ability correlates strongly with the activity of mTOR, which could point the way to advancement in the treatment of depression.
About this depression and serotonin research news
Author: Mario Mueller
Source: Wiley
Contact: Mario Mueller – Wiley
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Development of a Fluorescent Probe with High Selectivity based on Thiol-ene Click Nucleophilic Cascade Reactions for Delving into the Action Mechanism of Serotonin in Depression” by Weiying Lin et al. Angewandte Chemie International Edition
Abstract
Development of a Fluorescent Probe with High Selectivity based on Thiol-ene Click Nucleophilic Cascade Reactions for Delving into the Action Mechanism of Serotonin in Depression
The intrinsic correlation between depression and serotonin (5-HT) is a highly debated topic, with significant implications for the diagnosis, treatment, and advancement of drugs targeting neurological disorders.
To address this important question, it is of utmost priority to understand the action mechanism of serotonin in depression through fluorescence imaging studies.
However, the development of efficient molecular probes for serotonin is hindered by the lack of responsive sites with high selectivity for serotonin at the present time.
Herein, we developed the first highly selective serotonin responsive site, 3-mercaptopropionate, utilizing thiol-ene click cascade nucleophilic reactions. The novel responsive site was then employed to construct the powerful molecular probe SJ-5-HT for imaging the serotonin level changes in the depression cells and brain tissues.
Importantly, the imaging studies reveal that the level of serotonin in patients with depression may not be the primary factor, while the ability of neurons in patients with depression to release serotonin appears to be more critical. Additionally, this serotonin release capability correlates strongly with the levels of mTOR (intracellular mammalian target of rapamycin).
These discoveries could offer valuable insights into the molecular mechanisms underpinning depression and furnish mTOR as a novel direction for the advancement of antidepressant therapies.
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