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Rapid presynaptic maturation shown in naturally regenerating axons


One of the requirements of successful neuronal regeneration is for newly-grown axons to establish functional connections with their downstream synaptic partners. To do this effectively, presynaptic neurotransmitter release needs to be reconstituted. In the adult mammalian central nervous system, where regeneration is generally only possible through experimental manipulation, we know very little about how regenerating pre-synaptic terminals re-establish contact with target circuits.

Lorcan Browne (now a scientific advisor to the UK government), Andres Crespo (now at the Francis Crick Institute) and Matt Grubb set out to study this process of presynaptic maturation using a model of entirely natural regeneration. Following injury from toxin exposure, olfactory sensory neurons in the adult mouse olfactory epithelium can completely regenerate and send axons via the olfactory nerve to re-establish synaptic contact with postsynaptic partners in the olfactory bulb. Exploiting this, Browne et al., available now in Cell Reports, used electrophysiological recordings in acute slices of the adult mouse olfactory bulb to understand how regenerating axons re-connect with their downstream targets.

The authors found that after initial re-contact, functional connectivity in the system was rapidly established. Intriguingly, presynaptic terminals that were reconnecting after injury had functional properties similar to their mature counterparts, such as a strong capacity for presynaptic inhibition and high release probability. In further experiments, Browne et al. found that release probability in these terminals develops remarkably quickly - the re-established terminals were indistinguishable from controls just a week after initial contact was made.

Browne et al., using a natural regeneration model, demonstrate the speed and efficiency of synaptic regeneration in the adult mammalian brain and liken it to a ‘plug-and-play’ process. They provide a comprehensive functional perspective on maturation in regenerating olfactory sensory neuron presynaptic terminals and show that presynaptic terminals undergo a rapid phase of functional maturation as they re-integrate into target networks.