Synaptic vesicle undocking as a mechanism for low-frequency synaptic depression

• Applicant: Dr. Melissa Silva Medina Weil, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 578410388

Neurons communicate via specialized connections known as synapses. The strength of these connections is highly dynamic and can be modulated on different time scales. Short-term plasticity describes the strengthening (facilitation) or weakening (depression) of synaptic transmission within milliseconds to seconds. While synapses can operate over a wide frequency spectrum, neurons in living organisms are mainly active at low frequencies. In this range it is assumed that synaptic strength remains stable due to fast recovery processes. Therefore, short-term plasticity research has so far focused on the high frequency range, leaving the dynamic behavior at low frequencies largely unexplored. However, emerging evidence suggests that synapses can also be modulated upon low-frequency activity. Intriguingly, morphological data indicates a common, presynaptic mechanism for high-frequency facilitation and low-frequency depression within the same synapse. Presynaptic short-term plasticity involves multiple mechanisms, including accumulation of calcium ions and synaptic vesicle depletion. Before fusing with the presynaptic membrane, synaptic vesicles interact with specialized structures known as docking sites. Vesicle docking may regulate synaptic transmission and underlie both facilitation and low-frequency depression. However, how this docking process affects synaptic transmission and plasticity remains poorly understood. This proposal aims at characterizing the behavior of synapses across the frequency spectrum and elucidating the role of synaptic vesicle docking in short-term plasticity. Using mouse and human neuronal models, we will combine advanced techniques like electrophysiology, proteomics, and computational modeling to uncover mechanisms shaping neural communication. The results will have broad implications for neuroscience, potentially guiding new approaches to treating neurological disorders and advancing artificial neural network designs.

• DFG Programme: WBP Position