Glial response to hypoxia in trachealess mutants induces synapse remodeling.

Abstract

Synaptic structure and activity are sensitive to environmental alterations. Modulation of synaptic morphology and function is often induced by signals from glia. However, the process by which glia mediate synaptic responses to environmental perturbations such as hypoxia remains unknown. Here, we report that, in the Drosophila trachealess (trh) mutant, smaller synaptic boutons form clusters named bunch boutons appear at larval neuromuscular junctions (NMJs), which is induced by the reduction of internal oxygen levels due to defective tracheal branches. Thus, the bunch bouton phenotype in the trh mutant is suppressed by hyperoxia, and recapitulated in wild-type larvae raised under hypoxia. We further show that hypoxia-inducible factor (HIF)-1/Similar (Sima) is critical in mediating hypoxia-induced bunch bouton formation. Sima upregulates the level of the Wnt/Wingless (Wg) signal in glia, leading to reorganized microtubule structures within presynaptic sites. Finally, hypoxia-induced bunch boutons maintain normal synaptic transmission at the NMJs, which is crucial for coordinated larval locomotion. Author summaryOxygen is essential for animals to maintain their life such as growth, metabolism, responsiveness, and movement. It is therefore important to understand how animal cells trigger hypoxia response and adapt to hypoxia thereafter. Both mammalian vascular and insect tracheal branches are induced to enhance the oxygen delivery. However, the study of hypoxia response in the nervous system remains limited. In this study, we assess the morphology of Drosophila neuromuscular junctions (NMJs), a model system to study development and function of synapses, in two hypoxia conditions, one with raising wild-type larvae in hypoxia, and the other in the trachealess (trh) mutant in which the trachea is defective, causing insufficient oxygen supply. Interestingly, glia, normally wrapping the axons of NMJs, invade into synapse and trigger Wg signals to reconstitute the synaptic structure under hypoxia. This synaptic remodeling maintains the synaptic transmission of synapse, which associate the locomotor behavior of larvae.