Gliotransmission and adenosine signaling promote axon regeneration

How glia control axon regeneration remains incompletely understood. Here, we investigate glial regulation of regenerative ability differences of closely related Drosophila larval sensory neuron subtypes. Axotomy elicits Ca2+ signals in ensheathing glia, which activates regenerative neurons through the gliotransmitter adenosine and mounts axon regenerative programs. However, non-regenerative neurons do not respond to glial stimulation or adenosine. Such neuronal subtype-specific responses result from specific expressions of adenosine receptors in regenerative neurons. Disrupting gliotransmission impedes axon regeneration of regenerative neurons, and ectopic adenosine receptor expression in non-regenerative neurons suffices to activate regenerative programs and induce axon regeneration. Furthermore, stimulating gliotransmission or activating the mammalian ortholog of Drosophila adenosine receptors in retinal ganglion cells (RGCs) promotes axon regrowth after optic nerve crush in adult mice. Altogether, our findings demonstrate that gliotransmission orchestrates neuronal subtype-specific axon regeneration in Drosophila and suggest that targeting gliotransmission or adenosine signaling is a strategy for mammalian central nervous system repair. [Display omitted] •Axotomy elicits Ca2+ signals in Drosophila ensheathing glia•Gliotransmission elicits neuron subtype-specific regenerative programs in Drosophila•Firing patterns, but not overall excitability, dictate the axon regeneration outcomes•Stimulation of gliotransmission or Adora2b activation promotes RGC axon regrowth Sensory neuron subtypes in Drosophila show different axon regenerative abilities. Here, Wang et al. identify a mechanism by which a glia-neuron interaction through gliotransmission could promote axon regrowth after injury in Drosophila and show that this may also be true in a mouse model.