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, which are highly specialized connections that allow transfer of information between neurons. Synapses are constantly changing and are lost 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. Neuronal activity can make synaptic connections stronger. This activity-triggered synaptic strengthening is thought to underlie memory formation. We recently discovered that synaptic activity causes neurons to secrete a protein named netrin-1. We then found that neurons must make netrin-1 for synaptic strengthening to work, and that memory deficits develop when netrin-1 is genetically removed from neurons in adult mice. To our surprise, we found that adding netrin-1 to adult neurons is sufficient, without activity, to potently strengthen synapses. Together, these findings identify a new molecular mechanism that appears to be central to synaptic function and memory formation. Human genetic studies by other groups have identified mutations in the genes encoding netrins and netrin receptors in individuals affected by autism, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This suggests the possibility of recovering function by modulating netrin activity, however little is known about how netrins work in the adult nervous system. We propose to investigate and identify the molecular mechanisms that underlie netrin-1 function at synapses in the adult brain. We have developed experimental tools and animal models and are in a unique position to make groundbreaking discoveries that will create new knowledge of how synapses are maintained and modified, and identify therapeutic targets to prevent loss of function associated with aging and disease.