Grant: Travel Awards - Institute Community Support

Synaptic connections are continuously modified, a feature of synapses that is required for higher brain functions such as learning and memory. While synaptic structure and function continuously change, many signaling mechanisms work in concert to stabilize synaptic function to reach a balance or homeostasis. Amounting evidence suggests that malfunction of these homeostatic mechanisms may underlie neuropathology and neurodegeneration. Revealing the molecular mechanisms at play is central to understanding nervous system function, both in health and in pathological states. Taking advantage of Drosophila genetics, we have uncovered that the target of rapamycin (TOR) critically regulates synaptic homeostasis at the Drosophila larval neuromuscular junction. TOR acts by enhancing cap-dependent translation by phosphorylating two down-stream bona fide targets: 4E-BP (the eukaryotic translation initiation factor 4E -binding protein), and S6K (the p70 ribosomal S6 kinase). Phosphorylated 4E-BPs no longer inhibit cap-dependent translation initiation. According to our model, loss of 4E-BP function should enhance synaptic function. We therefore asked whether loss of 4E-BP function alone is sufficient to enhance synaptic transmission. To test this idea, we have conducted our studies in 2 ways. In one, we characterized synaptic function at the Drosophila neuromuscular junction of 4E-BP loss of function mutants. In the second, we tested whether Cap-dependent translation mechanisms play a similar at neuronal-neuronal synapses in mammals as it does in Drosophila. For the latter experiments, we are examining synaptic strength at synapses in sympathetic ganglia of 4E-BP1/BP2 double mutant mice. Our results at the Drosophila neuromuscular junction indicate that 4E-BP acts as a constitutive negative regulator of synaptic strength. Interestingly, our results from synapses in the 4E-BP1/BP2 double mutant mice suggest that that 4E-BP's function is conserved from flies to mice.