Insulin signalling promotes dendrite and synapse regeneration and restores circuit function after axonal injury

See Peterson and Benowitz (doi:10.1093/brain/awy165) for a scientific commentary on this article. Dendrites retract and disconnect from their cellular partners in a number of psychiatric and neurodegenerative diseases. Agostinone et al. show that injured mammalian retinal ganglion cells have the capacity to regenerate dendrites and reestablish functional connections, and identify insulin signalling as paramount for a successful pro-regenerative response. Abstract Dendrite pathology and synapse disassembly are critical features of chronic neurodegenerative diseases. In spite of this, the capacity of injured neurons to regenerate dendrites has been largely ignored. Here, we show that, upon axonal injury, retinal ganglion cells undergo rapid dendritic retraction and massive synapse loss that preceded neuronal death. Human recombinant insulin, administered as eye drops or systemically after dendritic arbour shrinkage and prior to cell loss, promoted robust regeneration of dendrites and successful reconnection with presynaptic targets. Insulin-mediated regeneration of excitatory postsynaptic sites on retinal ganglion cell dendritic processes increased neuronal survival and rescued light-triggered retinal responses. Further, we show that axotomy-induced dendrite retraction triggered substantial loss of the mammalian target of rapamycin (mTOR) activity exclusively in retinal ganglion cells, and that insulin fully reversed this response. Targeted loss-of-function experiments revealed that insulin-dependent activation of mTOR complex 1 (mTORC1) is required for new dendritic branching to restore arbour complexity, while complex 2 (mTORC2) drives dendritic process extension thus re-establishing field area. Our findings demonstrate that neurons in the mammalian central nervous system have the intrinsic capacity to regenerate dendrites and synapses after injury, and provide a strong rationale for the use of insulin and/or its analogues as pro-regenerative therapeutics for intractable neurodegenerative diseases including glaucoma.