When we form a memory, brain cells need to deliver supplies to strengthen specific neural connections. A new study from MPFI and Weill Cornell Medicine has revealed how two cellular switches, Rab4 and Rab10, direct supplies to where they are needed.
Key Findings
- New tools track cellular supply routes: Scientists created biosensors to measure Rab proteins, cellular switches that direct the delivery of supplies inside cells. Beyond the findings in this paper, these sensors allow observation of the activity along complex supply routes, critical for many cellular functions.
- Rab4 provides a boost in the first minutes: During the strengthening of neuronal connections, Rab4 is activated, rapidly delivering the necessary supplies.
- Rab10 acts a brake: Rab10 shunts supplies away from the neural connection and is turned off for more than 30 minutes to enhance the strengthening of neural connections.
- Broader impacts: As Rab10 gene variants are linked to resilience against Alzheimer's Disease, these findings are critical to further research into strategies to protect memories in dementia.
When we form a memory, specific, highly active connections between our neurons are strengthened through a process called synaptic potentiation. This strengthening involves structural changes to physically enlarge the connection and make it more responsive to incoming messages. Accomplishing this requires a complex logistical operation within the neuron to quickly and precisely deliver the necessary supplies to remodel the strengthening connection.
Cellular Railroad Switches
A large family of cellular switches, known as Rab proteins, regulates the flow of supplies in cells. Like railroad switches, different Rab proteins direct supplies toward one destination or another. To examine how these cellular switches direct supplies during synaptic potentiation, the researchers developed biosensors to measure the activity of Rab switches and specific supplies needed for strengthening neural connections.
"These biosensors give us a window into how these molecular switches behave in real time, at the level of single spines," said Dr. Jie Wang, lead author of the study. "By understanding which and how Rab proteins are regulated during synaptic potentiation, we can begin to understand the logistical complexity that is required to strengthen neuronal connections when we form a memory."
The scientists found that changes in Rab4 and Rab10 switches were both critical during the strengthening of neural connections. However, the two switches worked in opposite directions. When Rab4 was activated, it boosted the strengthening of neural connections, whereas Rab10 activation decreased it.
"Our findings suggest that during synaptic plasticity, we have a local and coordinated logistical operation to rapidly turn on Rab4 to increase the delivery of supplies to the surface of the growing connection and at the same time turn off the Rab10 switch that might be directing supplies away from the surface and toward disposal," describes MPFI scientific Director and senior author Dr. Ryohei Yasuda.
To directly test this idea, the scientists tracked the delivery of neurotransmitter receptors, a crucial supply for strengthening neural connections. These receptors receive the information sent from connected neurons. The more receptors present, the easier a message is received. The team found that when Rab4 was activated, more receptors were directed to the neural connection. On the other hand, activation of Rab10 directed these receptors away from the connection.
Relevance to Alzheimer's Resilience
These discoveries reveal the critical role of Rab cellular switches in strengthening connections during memory formation. Because gene variants in Rab10 have also been implicated in providing resilience against Alzheimer's disease, the work may point toward new strategies for protecting memory in neurodegenerative conditions.
"I am excited about the potential for the tools and findings from this project, particularly for Rab10, to advance studies in Alzheimer's resilience and Rab10 as a potential as a therapeutic target," described Dr. Yasuda. "Beyond that, we have created a library of tools that will help us, and other scientists, study the complex logistical operations essential for all cellular functions."
Just as rail switches guide freight trains to the right track, more than 60 different Rab proteins direct cellular cargo. The Yasuda lab is sharing these biosensors to provide scientists a way to watch cellular logistics in action.
Publication:
Wang, J., Nishiyama, J., Parra-Bueno, P., Okaz, E., Oz, G., Liu, X., Watabe, T., Suponitsky-Kroyter, I., McGraw, T. E., Szatmari, E. M., & Yasuda, R. (2025). Rab10 inactivation promotes AMPAR trafficking and spine enlargement during long-term potentiation. eLife, 13, RP103879. 10.7554/eLife.103879 10.7554/eLife.103879 ).
This work was supported by grants from Japan Society for the Promotion of Science Overseas Research Fellowship, National Institute of Health, a donation from the Luen Fung Group and the Max Planck Florida Institute for Neuroscience. This content is solely the authors' responsibility and does not necessarily represent the official views of the funders.
