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For the brain to function normally, it needs a protein called BDNF. Low levels of this protein have been linked to depression, schizophrenia and Alzheimer’s disease. A recent discovery by scientists could help lead to the development of future medications that prompt the brain to start producing it on command.
The protein BDNF plays a vital role in brain function. It acts like a fertilizer that helps brain cells grow by creating new connections between neurons and maintaining existing ones. This process underpins the brain’s adaptability, which in turn influences learning, memory and even behavior.
Disruptions in the balance of this protein have been linked to a range of neurological and psychiatric disorders, including depression, anxiety disorders and neurodegenerative diseases such as Alzheimer’s and Huntington’s.
Researchers at Tallinn University of Technology (TalTech) have discovered a new layer of gene regulation that helps the brain control how and when BDNF is produced. Lead author Eli-Eelika Esvald explained that while BDNF has long been known to be essential for brain health and that low levels are associated with depression, schizophrenia and Alzheimer’s, it had remained unclear what exactly controls BDNF production. “We’ve now taken several steps forward,” she said.
To make this discovery, the researchers studied rats, focusing on the molecular mechanisms that switch the BDNF gene on and off. In particular, they examined two key signals that influence BDNF production: the activity of neurons, which is critical for processes such as learning, and the protein’s own feedback signals.
The research team identified key proteins that bind to regions of the gene that regulate BDNF expression and direct its activity. They also confirmed these proteins’ interaction with the BDNF gene in the brain tissue of test animals. In total, the Tallinn University of Technology scientists identified three key proteins: ATF2, MYT1L and EGR1. While the roles of these proteins in the nervous system have been studied before, the team’s findings offer a much more detailed view of how BDNF production is regulated in the brain.
Metaphorically speaking, the proteins behave like members of an orchestra. When neurons begin to decline or receive a chemical signal, conductors step in to either boost or suppress BDNF gene expression as needed. The study showed that the proteins do not act in isolation, they form a dynamic and finely tuned system by binding to the same regulatory regions of the BDNF gene. Sometimes they compete; at other times they reinforce one another, just like in a well-coordinated orchestra.
Depending on which protein or combination of proteins binds to the gene at any given moment, BDNF production may increase, decrease or remain steady. This complex interplay of competition and cooperation allows the brain to finely adjust BDNF levels in response to current needs.
For the first time, the study also showed that some of the proteins regulating the BDNF gene respond in highly specific ways to different signals. For instance, the USF family of proteins is mainly activated by increased neuronal activity, while AP1 proteins respond primarily to feedback from BDNF itself. This specificity enables the brain to more precisely distinguish between different situations and respond accordingly.
A better understanding of how BDNF levels are regulated could lead to more targeted treatments for depression and neurodevelopmental disorders. Instead of artificially administering the protein or broadly affecting neurons, it may become possible in the future to develop medications that selectively target the regulatory proteins or mechanisms uncovered in this study.
“We don’t just want to add BDNF from the outside, we want to understand how the brain could be prompted to produce it naturally and at the right time,” explained research group leader Tõnis Timmusk. In other words, instead of using a hammer to influence the brain, pharmacologists could one day use a surgeon’s scalpel.
The study was published in The Journal of Neuroscience.
Author: Airika Harrik / Editor: Sandra Saar, Marcus Turovski. This article was originally published on the the Estonian Public Broadcasting online news portal.
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