Molecular Mechanisms of Synaptic Plasticity
The modification of synaptic connections between neurons is thought to underlie the ability to form memories and learn new behaviors. In the central nervous system, most synapses terminate on dendritic spines, tiny (~0.5 μm in diameter) mushroom-shaped protrusions emanating from the dendritic surface. Calcium influx into spines activates various signaling pathways that underlie synaptic plasticity. The major goal of our laboratory is to understand the molecular mechanisms of signaling in spines.
We are currently focusing on two approaches. First, we study function and regulation of calcium channels and synaptic receptors using two-photon-based Ca2+ imaging in combination with electrophysiology. We recently found that calcium channels are down regulated by high neuronal activity, and that this regulation modulates synaptic plasticity.
Second, to study spatio-temporal dynamics of enzymatic activity, we develop and use two-photon fluorescence lifetime imaging microscopy (TPFLIM). TPFLIM allows us to quantify protein-protein interactions in living cell at the single-synapse resultion in highly scattered brain tissue. We recently have suceeded to image activity of Ras in individual spines. Now we are studying how the Ras activity may spread from a stimulated spine by combining TPFLIM with two-photon glutamate uncaging technique.
Studying biochemical signaling in spines has been difficult because each spine often contains only a few copies of each protein. Furthermore, one protein can play roles in many pathways, and likely only a subpopulation of the protein is activated in a specific pathway. Using two-photon based biophysical techniques, we hopefully will be able to disentangle the complex signaling network in synapses and give insights into mental disorders.
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