Synapses are the sites of memory storage and their ability to adapt (synaptic plasticity) while maintaining long-term stability presents a fascinating problem. A confound is that molecular components (proteins, lipids) have limited lifetimes, leaving how information encoded at synapses is stable long-term, as an open question. Spines are a specialized structure on the post-synaptic side of the synapse (examples extending from the dendrite in the figure) that help solve this problem by providing isolated compartments for biochemical signal processing and localized adaptations to take place. In addition to investigating these basic neuroscience questions, we are also studying how the system of synaptic molecules becomes unbalanced following brain injury or during neurodegenerative processes.
To uncover the mechanisms underlying synaptic plasticity we use an array of state-of-the-art imaging and biophysical approaches to address the problem at the molecular and cellular level. Confocal and super-resolution fluorescence imaging and multi-photon fluorescence spectroscopy reveal the distribution and dynamics of protein or organelle movement. High-resolution cryo-electron microscopy and tomography reveal the structural details of molecules and organelles in isolation and in their native cellular environment. Together with detailed analysis of enzyme kinetics and protein-protein interactions assessed using biochemical and reconstitution approach, a comprehensive model of synaptic biology and synaptic plasticity will be attained.
Heberle, FA., Doktrova, M., Scott, H.L., Skinkle, A.D., Waxham, M.N., and Levental, I. (2020). Direct label-free imaging of nanodomains in biomimetic and biological membranes by cryogenic electron microscopy. Proc. Natl. Acad. Sci. USA