Molecular mechanisms underlying the choice between homeostasis and activity-dependent plasticity at the synapse

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From flies to humans, synapses are shaped by plastic events that promote or limit changes in synaptic strength. Indeed, changes in neuronal activity can lead to modifications in the property/strength of the synapse. This ability is called activity-dependent synaptic plasticity (ADSP). Another form of plasticity, referred to as synaptic homeostasis (SH), aims at maintaining synaptic output to ensure stable activity. These two distinct forms of synaptic plasticity are at the center of processes of cognition. Indeed, ADSP is regarded as the cellular correlate of learning and memory while perturbations of SH are linked to an array of neurological diseases. To date, most studies have considered these two forms of plasticity separately. The question remains: how does a synapse integrate the two to ensure the stability of its output while still allowing for discrete changes in synaptic strength when required? Here we propose to study, at a single synapse level, the apparent antagonism between ADSP and SH. In addition, we will highlight two opposing molecular controllers underlying the mutually exclusive choice between these two modes of plasticity. Using the Drosophila Neuromuscular junction (NMJ), we propose to show that the transcription factor gooseberry (gsb, the pax3/7 homolog) and the signaling molecule wingless (wg, the wnt homolog) have antagonistic functions which determine synaptic plasticity. Using genetics, immunohistochemistry and electrophysiology, we will first ask whether eliciting SH perturbs subsequent ADSP and vice versa. This will allow us to characterize the mutual exclusivity of the two forms of plasticity and know whether one form supersedes the other or whether the order in which they are engaged is the determining factor. We will then show that a gene characterized as essential to SH, gsb, inhibits ADSP. Similarly, we will ask whether the pro-ADSP signal Wg antagonizes SH. Finally, we will characterize genetic interactions between gsb and wg supporting the idea of antagonism between the two molecules. This work will determine whether there is a hierarchical or temporal organization that determines the predominant plasticity. It will also contribute to understanding one of the molecular systems underlying this organization. It will be a major contribution to our understanding of the integration of ADSP and SH. Furthermore, it will place us in an ideal position to dissect the function and regulation of the synaptic targets directed by Wg and Gsb during these processes of plasticity.