Grant: Project Grant

The day to day function of the nervous system depends on the ability of nerve cells to communicate with each other. Neuron-to-neuron communication is possible through synapses, highly specialized structures that allow transfer of information from one cell to another. Synapses are constantly changing and they are dramatically altered in neurodegenerative diseases. A long-term focus of my research program is to understand how synapses are formed, how they change and how they can be maintained in the aging and injured brain. We recently discovered that a family of proteins named netrins is essential for synapse formation during development. Importantly, we also found that netrins are made in the adult brain and play a crucial role regulating memory. Exciting new studies in humans have identified mutations in the genes encoding netrins and netrin receptors in individuals affected by Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. These findings open up the possibility of recovering neuronal function, learning and memory through the modulation of netrin activity. A major roadblock towards this goal is that very little is known about how netrins work in the adult nervous system. To gain an in-depth understanding of how netrins promote synapse function and modulate communication between neurons in the aging and diseased brain, we will identify the consequences of genetic deletion of netrin-1 from neurons in the mouse brain. We will determine if neuronal activity regulates the function of netrin at synapses, and investigate the contribution of these mechanisms to deficits associated with early stages of Alzheimer's disease. My laboratory has developed experimental tools and animal models that place us in a unique position to make groundbreaking discoveries. The proposed studies will create new knowledge of how synapses are maintained and modified and will identify therapeutic targets to prevent loss of function in aging and disease.