Modeling Activity-Dependent Synaptic Competition via a Novel Coculture System

Abstract

Immature neural circuits undergo synaptic refinement, in which activity-dependent competition between synapses results in pruning of inappropriate connections and maintenance of appropriate ones. A longstanding question is how neuronal activity eliminates specific synapses based on their strength. The technical challenges of in vivo studies have made it difficult to identify a molecular link between decreased activity and synapse elimination. We developed an organotypic coculture model of the mouse retinogeniculate system that facilitates real time imaging and elucidation of molecular mechanisms underlying the removal of less active synapses during synaptic competition. Using this model, we show complement component C1q is necessary for activity-dependent synaptic competition and preferentially localizes to less active, competing presynaptic inputs. For the first time, we directly observe retinal ganglion cells undergoing activity-dependent competition via time lapse imaging. We also investigate whether a novel synaptic apoptosis, or ‘synaptosis,’ mechanism mediates elimination of less active synapses via local caspase-3 activation and externalization of the membrane phospholipid phosphatidylserine to recruit complement. Elucidation of the mechanisms by which specific synapses are eliminated during developmental pruning could facilitate identification novel therapeutic targets in diseases involving abnormal synapse refinement, particularly synapse loss and dysfunction.