Florida Researchers Uncover Key Protein’s Role in Neural Connections

Neuroscientists at Florida Atlantic University have made a significant discovery regarding a protein known as “Frazzled,” which is referred to as DCC in mammals. Their research reveals how this protein plays a crucial role in the formation of synapses, the connections between neurons, essential for efficient communication in the nervous system of Drosophila, commonly known as fruit flies. The findings, published in the journal eNeuro, highlight fundamental mechanisms that ensure neurons connect effectively.

The study focused on the Giant Fiber (GF) System of fruit flies, a neural circuit responsible for the rapid escape reflex. Researchers demonstrated that when Frazzled is absent or mutated, several critical issues arise. Neurons fail to establish proper electrical connections, leading to slower neural responses and weakened communication between GF neurons and the muscles they control. These problems stem from a reduction in gap junctions, which are microscopic channels that enable direct and rapid signal transmission between neurons.

To delve deeper into Frazzled’s function, the research team utilized a genetic tool called the UAS-GAL4 system to introduce various segments of the Frazzled protein back into mutant flies. Remarkably, they found that just the intracellular portion of Frazzled—responsible for influencing gene expression—was sufficient to restore both the structure of the synapses and the speed of neuronal communication. Disruption of this intracellular domain, particularly by removing a specific region known as P3 or altering a critical site within it, hindered the restoration efforts. This indicates that Frazzled’s control over gene activity is vital for building gap junctions.

The researchers also developed a computational model of the GF System, simulating the impact of varying gap junction numbers on neuronal firing reliability. The model confirmed that even minor changes in gap junction density can significantly affect the speed and precision of neural signaling.

Rodney Murphey, Ph.D., the senior author and a professor at the Charles E. Schmidt College of Science, commented on the significance of their findings. He stated, “The combination of experimental and computational work allowed us to see not just that Frazzled matters, but exactly how it shapes the connections that let neurons talk to each other.” The next steps for the team involve exploring whether similar mechanisms govern neural circuits in other species, including mammals, and investigating their implications for learning, memory, and recovery from neural injuries.

The study also reveals that, while Frazzled has long been recognized for its role as a guidance molecule—assisting neurons in growing along the correct paths—its intracellular domain is directly involved in regulating synapse formation. Flies deficient in Frazzled often exhibited neurons growing in erratic directions, failing to reach their intended targets. By restoring the intracellular domain, many of these misguidance errors were corrected, highlighting Frazzled’s dual role in both wiring neurons and refining their communication.

These findings also draw parallels with similar proteins found in other organisms, including worms and vertebrates, suggesting that Frazzled and its counterparts may have a broadly conserved function in shaping neural networks. By elucidating how a single protein can influence both the physical and functional aspects of electrical synapses, this research provides valuable insights into the foundational principles governing the assembly of nervous systems.

Murphey emphasized the importance of understanding how neurons establish reliable connections, stating, “Frazzled gives us a clear handle on one piece of that puzzle. Our findings could inform future studies of neural development, neurodegenerative diseases, and strategies to repair damaged circuits.”

The co-authors of this study include first author Juan Lopez, Ph.D., a postdoctoral researcher at FAU; Jana Boerner, Ph.D., managing director of the Advanced Cell Imaging Core within the FAU Stiles-Nicholson Brain Institute; Kelli Robbins, research staff in FAU’s Department of Biological Sciences; and Rodrigo Pena, Ph.D., an assistant professor in the same department.

Florida Atlantic University continues to be a leader in research and education, serving over 32,000 undergraduate and graduate students across its six campuses along Florida’s Southeast coast.