Regulation of structural plasticity and actin cytoskeleton by plasma membrane cholesterol turnover in dendritic spines

All cells are surrounded by a membrane of lipids and proteins that controls the cell's interaction with the environment. The membrane rapidly adjusts to the environment and the cell's needs by changing its composition and shape. Cholesterol is an essential component of all animal membranes and regulates their flexibility, permeability and other characteristics. Our research program focuses on cholesterol in nerve cell membranes. We investigate how cholesterol levels in the membrane are regulated and how changes in membrane cholesterol levels influence nerve cell communication. Nerve cells have a very intricate shape which is optimized to connect with many other nerve cells to form a large communication network in the brain. To be able to receive input from many other cells, nerve have long, branched processes called dendrites, which have additional small membrane protrusions called dendritic spines. At the tip of these spines, the nerve cell connects with another nerve cell to receive a signal. One neuron has many dendrites, each with many spines, so each neuron can receive input from with many other nerve cells. The number of spines and their size influence the strength of the incoming signal. Nerve cells can rapidly adjust the shape of the spines according to an incoming signal. This process is called synaptic plasticity and is the basis for learning and memory. Other studies have shown that nerve cells release cholesterol from the membrane when they receive strong signals from other cells, and later recover that cholesterol. However, it is not known how the initial release affects the shape and function of the spines, and it is not known how nerve cells quickly regain cholesterol after having released it; they could take it up from surrounding support cells or make it themselves. We aim to address these questions by culturing nerve cells in the presence of their normal support cells, and experimentally induce defects in cholesterol release or in the production of cholesterol inside nerve cells. We will then characterize the effects of these changes on the size and number of dendritic spines, and determine whether they can still adjust to incoming signals. We also aim to determine how cholesterol content in the spines changes during nerve cell activity. Preliminary experiments suggest that spine growth in response to signals is impaired when cholesterol production is disrupted, even though the nerve cells can still get cholesterol from outside. We aim to elucidate the mechanisms through which how cholesterol influences the spine, and why external cholesterol may not be able to fully replace external cholesterol coming from the other cells. Our work addresses a fundamental aspect of nerve cell function. Moreover, given that nerve cells are not the only cells that change their shape rapidly in response to signals, some of these mechanisms may also be important in other cell types.