Regulation of synapse formation and function by cholesterol

This proposal investigates how cholesterol influences the communication between nerve cells in the brain. Nerve cells communicate through synapses, which are sites where two neurons come very close to each other. To transmit a signal across the synapse, one nerve cell releases small molecules called neurotransmitters and the second nerve cell senses these neurotransmitters and responds. Neurotransmitters are stored inside small vesicles in the synapse. To release the neurotransmitter, these vesicles integrate into the outer nerve cell membrane and thus open to the outside of the cell. Vesicles are then quickly retrieved from the outer membrane, and refilled with neurotransmitter to transmit another signal. Vesicle retrieval must be closely regulated to ensure that all proteins are sorted correctly into the vesicle. We are interested in the mechanisms of vesicle formation and in the role that cholesterol plays in this process. Nerve cell membranes and vesicles contain high levels of cholesterol, which influences the fluidity and shape of the membranes, and the function of membrane proteins. We aim to find out how nerve cells regulate cholesterol in their membranes, and how cholesterol affects the retrieval of synaptic vesicles from the outer nerve cell membrane. To address these questions, we will grow isolated neurons, induce changes in their cholesterol metabolism, and measure the effects on different pathways of synaptic vesicle formation. The pathways most affected will be studied in detail to find out what aspects of cholesterol metabolism regulate vesicle formation. We will also investigate how cholesterol might influence the packaging of the different components into the vesicle. Deeper knowledge about the role of cholesterol in nerve cell communication may help to understand changes that occur during neurodegeneration or aging.