A retrograde GCN2/eIF2α, but ATF4 independent, mechanism maintains synaptic strength under acute amino acid scarcity at the NMJ

Neuronal response to nutrient availability plays an important role in the maintenance of cellular homeostasis and behavioral response to the environment in higher eukaryotes. However, we know little about how neuronal function is influenced by acute changes in nutrients at high resolution. Taking advantage of powerful fly genetics and the amenability of the Drosophila larval neuromuscular junction (NMJ), we have investigated the synaptic response to acute amino acid restriction. Our findings indicate that the presence of general control nonderepressible 2 (GCN2) and phosphorylation of its target eukaryotic initiation factor 2 alpha (eIF2) are essential for the ability of the NMJ to maintain normal neurotransmitter output when the larvae are deprived of amino acids. Surprisingly, activating transcription factor 4 (ATF4), which normally acts downstream of GCN2/eIF2, appears dispensable in this regulation. Furthermore, we show that GCN2/eIF2 dependent cascade acts retrogradely from muscle back to motoneuron to adjust synaptic release. These results provide a mechanistic insight into the intricate regulation of synaptic strength through the action of GCN2 when organisms are faced with amino acid scarcity.