Within less than twenty minutes of completing this article, your brain will start to store the information you’ve just read through coordinated bursts of neuron activity. This process, known as dendritic translation, involves increased protein production in dendrites, which are the branches extending from the neuron cell body that receive signals from other neurons at synapses. This process is crucial for memory, and its malfunction is associated with intellectual disorders, such as Fragile X syndrome.
That makes the inner workings of dendritic translation a “holy grail for understanding memory formation,” says Rockefeller’s Robert B. Darnell, whose team just published a study in Nature Neuroscience describing a new platform capable of identifying the specific regulatory mechanisms that drive dendritic translation. The team leveraged a method, dubbed TurboID, to discover an entire suite of previously unknown factors in memory formation, revealing now mechanisms that underlie how protein synthesis in dendrites contributes to learning and memory. The findings may also have implications for intelligence.Limitations in technology have historically hindered the ability to thoroughly track the activity at the synapse that is involved in the formation of memories,” explained Ezgi Hacisuleyman, the lead author of the study. Hacisuleyman, who conducted the research while working as a postdoctoral researcher in Darnell’s laboratory, is now an assistant professor at The UF Scripps Institute. “Our new methods can address this issue with incredibly high precision, allowing us to examine neurons in vitro that closely resemble what we observe in the brain.”
“Hacisuleyman’s research defines an entirely new biochemical pathway that aligns with, complements, and greatly expands upon what we already know about neurological disabilities such as Fragile X syndrome.Darnell, the Robert and Harriet Heilbrunn professor, notes, “We already knew about memory and learning.”
A unique method of processing RNA
Memory creation revolves around the hippocampus, a brain region so crucial to learning that when it was removed from individuals with epilepsy in the 1940s, they retained memories from their childhood but lost the ability to form new ones. It has since been established that memories form, at least in part, due to the synthesis of new proteins occurring locally in the dendrites of the hippocampus.
As a physician-scientist, Darnell observed the significance of dendritic translation firsthand while working.The speaker worked with patients who had been affected by their immune systems attacking their hippocampus. He noticed that after talking to a patient for 30 minutes and then leaving the room, it seemed as though the patient had no memory of him when he returned. This led him to focus on why the neurons in the hippocampus have their own unique system for regulating RNA metabolism, which is not found in any other cell in the body.
As it turns out, this unique system is central to how our brains create memories and learn new information. This discovery became the main focus of the Darnell lab, leading to the development of CLIP in 2003. CLIP is a method that allows researchers to study the proteins that bind to and influence RNA.But there were still limitations. Hacisuleyman explained, “There were many unknown details about how neurons respond to stimuli at the dendrites. We needed that information to understand how neurons function and where things often go wrong in neurologic disease.” The team extended the TurboID platform to work with RNA-sequencing, CLIP, translation, and protein analysis to better understand the role of changes in dendrites in learning. This allowed them to track activity in dendrites before, during, and after stimuli.Shortly after the neuron becomes active, it captures the crucial moments for protein synthesis in the cell, especially the stage that is important for memory formation.
An examination of these critical moments revealed a small disturbance in the dendrite. When activated, local ribosomes attach to mRNAs, an action that shows all the biochemical characteristics of memory formation. This action is predicted to cause the dendrite to produce not only new proteins, but also 1,000 small proteins known as micropeptides, the function of which is currently unknown. The team also discovered an RNA-binding protein that helps to strengthen the connection between these ri.bosomes and mRNA, and showed that if that protein is disabled, the proposed micropeptides will not form.
“We never knew these micropeptides could even exist,” Darnell says. “It opens up a new area of study, where we can explore what these peptides might be doing and how they could contribute to memory formation. It’s such a significant discovery that there are numerous potential paths to pursue.”
Among the many observations that researchers will delve into in future studies, one stood out: the team observed that a certain protein stood out for its extensive binding of mRNA in the dendrite. The protein, known as FMRP, is crucial toThe Fragile X syndrome is a common genetic cause of intellectual disability, which is influenced by brain development and function, as well as genetic mutations affecting FMRP. Darnell stated, “Our findings align with the molecular biology of FMRP and offer opportunities for further understanding of Fragile X.” In addition to the immediate implications, the use of dendritic-TurboID could help researchers study protein synthesis in various brain regions and its application to different diseases. Hacisuleyman added, “We now have the ability to closely examine many other sites, allowing for more in-depth analysis.”A new method like Hacisuleyman’s allows you to step into a room that no one has ever entered before,” Darnell states. “The lights come on, and the discoveries leave you speechless.