INHIBITORY SYNAPSE PLASTICITY: UNRAVELING THE MECHANISMS OF SYNAPSE ELIMINATION IN THE HIPPOCAMPUS

Learning involves transient increases in the activity of local networks, in which specific spine turnover and local removal of inhibitory synapses work together to store new memories. However, the molecular mechanisms that underlie the local removal of inhibitory synapses during spine plasticity remain unresolved. Recent studies have suggested that signaling pathways that are typically involved in apoptosis may also engage in the removal of subcellular components and synapse elimination. Indeed, local pruning of synapses by microglia was reported to be regulated via caspase-3 and pro-BDNF has also previously been linked to synapse elimination. Here we set out to test if these pathways regulate the turnover of synaptic boutons in inhibitory axons. We used high resolution two photon microscopy to monitor synaptic boutons in GFP-labeled inhibitory axons in mouse organotypic hippocampal slices. Bouton turnover was not altered by the continuous presence (bath application for 100 minutes) of caspase-3 activators or inhibitors. Ongoing experiments are testing if brief local application of caspase-3 activators and inhibitors can induce synaptic competition between boutons along the same axon. In a separate set of experiments, we observed that a short bath application of pro-BDNF (5 minutes) promoted inhibitory bouton destabilization and reduced the formation of new inhibitory boutons. These findings identify proBDNF as a regulator of rapid inhibitory presynaptic remodeling. We currently examine whether this is a general mechanism or specific for inhibitory neuron subtypes.