Gliotransmission orchestrates neuronal type-specific axon regeneration

SUMMARYWhy closely related neuronal types differ in their axon regenerative abilities remains elusive. Here, we demonstrate gliotransmission determines such a difference in Drosophila larval sensory neurons. Axotomy activates ensheathing glia, which signal to regenerative neurons through the gliotransmitter adenosine, to mount regenerative programs including neuronal activity and Ras. Surprisingly, ensheathing glia do not signal to non-regenerative neurons. Such neuronal type-specific responses to gliotransmission result from specific expression of adenosine receptors in regenerative neurons. Disrupting gliotransmission impedes regeneration of regenerative neurons. Strikingly, reconstitution of gliotransmission in non-regenerative neurons enables them to regenerate. Furthermore, activation of an adenosine receptor ortholog in adult mice promotes both regeneration and survival of retinal ganglion cells, uncovering a conserved pro-regenerative role of adenosine receptors. Our studies demonstrate gliotransmission as a novel mechanism by which glia instruct axon regeneration, with neuronal type-specificity, and suggest targeting purinergic signaling as a new strategy for mammalian central nervous system repair.HIGHLIGHTSEnsheathing glia differentially interact with Drosophila sensory neuron types through gliotransmissionGliotransmission mounts axon regenerative programs in selective neuronal typesNeuronal firing pattern but not overall excitability dictates axon regeneration outcomeAdenosine receptor activation in adult mice promotes both regeneration and survival of RGCs