Current Research

The Challenge

Synapses are the sites of memory storage and their ability to adapt (synaptic plasticity) while maintaining long-term stability is not a trivial problem. 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 computations and isolated adaptations to take place. 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. In parallel, we are investigating how the system of synaptic molecules becomes unbalanced following brain injury or during normal aging or neurodegenerative processes.

The Approach

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. 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 holistic model of synaptic biology and synaptic plasticity will be attained.

Representative Publications

Mitochondria squeezed at the axon bridge between two synaptic terminals.
Fischer, T.D., Dash, P.K., Liu, J. and Waxham, M.N. (2018) Morphology of Mitochondria in Spatially Restricted Axons Revealed by Cryo-Electron Tomography. PloS Biology.
Slice of an electron tomogram of CaMKII/Actin rafts formed on a lipid monolayer. Red arrows highlight CaMKII enzymes with actin filaments running parallel, blue circle indicates an orthogonal arrangement of fibers
Wang,Q., Chen, M., Schafer, N.P., Bueno, C. Song, S.S., Hudmon, A. Wolynes, P.G., Waxham, M.N. and Cheung, M.S. (2019) Calcium/calmodulin-dependent kinase II – Actin assemblies and their dynamic regulation by calmodulin in dendritic spines. Proc. Natl. Acad. Sci. USA.
Electrostatic fields shown on the surface of CaMKII overlaid on a filamentous form of CaMKII induced by zinc binding.
Hoffman, L., Li, L., Alexov, E., Sanabria, H., and Waxham, M.N. (2017) Cytoskeletal-like filaments of CaMKII are formed in a regulated and Zn2+-dependent manner. Biochemistry 56, 2149-2160.