The Ras superfamily of small GTPase proteins is important for many neuronal processes essential to synaptic plasticity, including long-term synaptic potentiation, formation of new synapses, and regulation of cell excitability. Among the Ras superfamily, a particularly important subfamily is a group of proteins called Rab, which regulate trafficking of membrane and glutamate receptors during synaptic plasticity. Consistent with the importance of Rab signaling in synaptic plasticity, abnormal Rab signaling is associated with diseases causing cognitive impairments and learning deficits. However, the spatiotemporal dynamics of Rab proteins during synaptic plasticity and their exact functions at individual dendritic spines are not fully understood. Thus, the objective of this project is to elucidate the mechanisms and roles of Rab protiens in dendritic spines during synaptic plasticity. We have developed highly sensitive biosensors for imaging activity of Rab4, Rab5, Rab8 and Rab10. Our preliminary data suggest that Rab proteins are activated or inactivated in different temporal windows during synaptic plasticity. Based on these preliminary data and previous literatures, our central hypothesis is that Rab proteins regulate the balance of membrane trafficking between different internal membrane compartments in dendritic spines to regulate functional and structural plasticity of dendritic spines, and this in turn modulates synaptic plasticity, learning and memory. In this project, we will further analyze signaling mediated by Rab proteins and their roles in trafficking of membrane and receptors during synaptic plasticity.
Our specific aims are 1) to reveal the spatiotemporal dynamics of Rab activity during synaptic plasticity and to identify upstream regulators of Rab proteins, 2) to elucidate the roles of Rab proteins in structure and function of spines and in membrane trafficking during synaptic plasticity, 3) to identify the roles of Rab proteins in glutamate receptor internalization and recycling using biochemical assays, and 4) to elucidate the roles of Rab proteins in synaptic plasticity, learning and memory. This work will advance our understanding of how Rab couples calcium with synaptic plasticity, learning and memory.
Synaptic plasticity is regulated by signaling mediated by a group of signaling proteins called small GTPase proteins. Rab proteins are one of the subgroups of these molecules, and play important roles in membrane trafficking required for synaptic plasticity. Several mental diseases are caused by abnormal signaling by these molecules. Our proposed research will improve our knowledge of the biochemical events that underlie Rab signaling and its role in synaptic plasticity, learning and memory, and will hopefully provide significant impact on the therapeutics of Rab-related mental diseases such as Alzheimer?s disease, Parkison disease and mental retardation.
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