Project 467244

Synaptic plasticity, the activity dependent changes in efficacy and strength of synaptic connections in the adult brain, is thought to underlie learning and memory formation. Netrin-1 is a protein that was first identified as a guidance cue that directs brain development but continues to be highly expressed in the adult brain alongside its receptor, deleted in colorectal cancer (DCC). Genetic deletion of netrin-1 from neurons in adult mice results in memory deficits and impaired long-term potentiation (LTP), a measure of synaptic plasticity. Disruption of LTP is also seen with specific deletion of DCC from pre-synaptic neurons, identifying a novel role for pre-synaptic DCC in regulating synapse function. The goal of the proposed study is to investigate the mechanisms by which pre-synaptic DCC contributes to LTP. I hypothesize that pre-synaptic DCC is involved in docking pre-synaptic neurotransmitter vesicles and that absence of pre-synaptic DCC reduces the number of docked synaptic vesicles. First, I propose to explore whether DCC sets a threshold for inducing LTP by investigating if increasing the stimulation is sufficient to induce LTP. This will be done in both juvenile and adult mice, to see if the pre-synaptic role of DCC emerges during aging. Second, to examine if absence of pre-synaptic DCC alters the number and distribution of synaptic vesicles, I propose to use electron microscopy to examine synapse structure. My proposed studies aim to provide new insight into the fundamental mechanisms that regulate synaptic plasticity. The findings obtained will impact our understanding of neuro-developmental and age-related deficits in learning and memory, and potentially identify novel therapeutic targets for neurodegenerative diseases.