INVESTIGATING A ROLE FOR NETRIN-1/DCC SIGNALING IN EXCITATORY HOMEOSTATIC SYNAPTIC UPSCALING

Neuronal circuits require homeostatic mechanisms to counterbalance destabilizing forces and maintain physiologically stable firing rates. Homeostatic synaptic scaling allows neurons to maintain the relative weight of synaptic inputs, while adjusting overall firing levels in response to long-term perturbations in activity. The secreted protein netrin-1 and the netrin receptor deleted in colorectal cancer (DCC) are made by neurons and enriched at synapses in the mature mammalian brain. Recent studies have identified essential roles for neuronal netrin-1 and DCC in long-term potentiation (LTP), a classic form of activity-dependent Hebbian plasticity. Netrin-1 is sufficient to potentiate synapses and induce synaptic insertion of AMPA receptors. As such, netrin-1 is a candidate to regulate homeostatic upscaling, a process that requires similar increases in post-synaptic strength. The present study investigates the involvement of netrin-1 in homeostatic upscaling associated with long-term decreases in neuronal activity. We have demonstrated that netrin-1 is secreted following long-term silencing of activity induced by tetrodotoxin (TTX). Furthermore, using genetic knockouts of netrin-1 or DCC we have shown that each protein is required for the increase in miniature excitatory post-synaptic current (mEPSC) amplitude that follows long-term TTX exposure. Ongoing investigations are examining the signaling downstream of DCC that is involved in TTX-induced upscaling. These findings aim to identify a novel molecular mechanism involved in homeostatic plasticity and a convergence point between Hebbian and homeostatic plasticity.