Awarded in 2026
Home Department: Molecular & Cellular Physiology
Faculty Advisor: Axel Brunger (Molecular & Cellular Physiology, Photon Science Directorate, and Neurology & Neurological Sciences)

Title: Molecular Signature of Synaptic Plasticity Using Time-Resolved Cryo-Electron Microscopy

Abstract:
To filter the information and ensure optimal brain functions, neurotransmission is constantly adjusted. This biological process, called short-term plasticity (STP), regulates the probability of neurotransmitter release within tens of milliseconds and can reinforce or silence certain synapses in our brains. It is well known which proteins are responsible for the fusion of synaptic vesicles with the plasma membrane. However, how the organization of this machinery controls the activity of the synapse and its plasticity remains a mystery.

Syntaxin-1 is a protein responsible for the assembly of the SNARE complex and the fusion of the synaptic vesicles with the plasma membrane. The number and organization of syntaxin-1 is suspected to play a key role in the regulation of the release probability, however current studies are technically limited. So far, published work could not elucidate the molecular mechanism underlying pre-synaptic STP. In this project, I will compare the nanoscale topography of syntaxin-1 at two hippocampal synapses exhibiting either a facilitation or a depression of the release over stimulations and elucidate the molecular signature of STP in the brain.

To determine the localization of syntaxin-1 in a native state, I will combine endogenous labeling of syntaxin-1 with 1.4 nm gold-nanoparticles and transmission cryo-electron microscopy. 

To mimic plasticity, I propose to install an LED system to stimulate the synapses with optogenetics before plunge-freezing and imaging. This cutting-edge method aspires to bridge the function of cells and molecules with their structural observations through cryo-EM.

Therefore, I expect syntaxin-1 to form larger clusters and more SNARE complexes at vesicles that have a high probability of release during plasticity. My work will pave the way towards the artificial manipulation of neurotransmission by adjusting the nano-topography of syntaxin-1 in diseases lacking a balanced neurotransmission such as schizophrenia, autism spectrum disorder or epilepsy.