TOR Is Required for the Retrograde Regulation of Synaptic Homeostasis at the Drosophila Neuromuscular Junction

• Published in: Neuron (Cambridge, Mass.) Mass.), 2012-04, Vol.74 (1), p.166-178
• Main Authors: Penney, Jay, Tsurudome, Kazuya, Liao, Edward H., Elazzouzi, Fatima, Livingstone, Mark, Gonzalez, Miranda, Sonenberg, Nahum, Haghighi, A. Pejmun
• Format: Article
• Language: English
• Subjects: Animals; cap-binding protein; Drosophila; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Eukaryotic Initiation Factor-4E - genetics; Eukaryotic Initiation Factor-4E - physiology; Exocytosis - physiology; Failure analysis; Gene Expression Regulation - physiology; Glutamic acid receptors; Heterozygosity; Homeostasis; Homeostasis - physiology; Initiation factor eIF-4E; Insects; Kinases; Larva - metabolism; Motor Neurons - metabolism; Mutation; Neuromuscular Junction - metabolism; Neuromuscular junctions; Neurosciences; Neurotransmitter release; Phosphorylation; Protein Kinases - genetics; Protein Kinases - metabolism; Protein Transport - physiology; Proteins; Receptors, Glutamate - metabolism; Ribosomal Protein S6 Kinases - metabolism; Ribosomal proteins; Rodents; Signal Transduction - physiology; Statistical analysis; Synaptic Transmission - physiology; TOR protein; TOR Serine-Threonine Kinases; Translation
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2012.01.030

Homeostatic mechanisms operate to stabilize synaptic function; however, we know little about how they are regulated. Exploiting Drosophila genetics, we have uncovered a critical role for the target of rapamycin (TOR) in the regulation of synaptic homeostasis at the Drosophila larval neuromuscular junction. Loss of postsynaptic TOR disrupts a retrograde compensatory enhancement in neurotransmitter release that is normally triggered by a reduction in postsynaptic glutamate receptor activity. Moreover, postsynaptic overexpression of TOR or a phosphomimetic form of S6 ribosomal protein kinase, a common target of TOR, can trigger a strong retrograde increase in neurotransmitter release. Interestingly, heterozygosity for eIF4E, a critical component of the cap-binding protein complex, blocks the retrograde signal in all these cases. Our findings suggest that cap-dependent translation under the control of TOR plays a critical role in establishing the activity dependent homeostatic response at the NMJ. ► TOR is required for the ability of the NMJ to undergo homeostatic signaling ► TOR acts in a retrograde manner ► S6K acts downstream from TOR ► TOR can induce a retrograde enhancement in neurotransmitter release Haghighi et al. find that target of rapamycin (TOR), a major cellular enzyme known to integrate many intracellular and extracellular cues, is a regulator of synaptic homeostasis and stability in the nervous system.