Li, S.-J. et al. Neuron 98, 905–917 (2018).

Retrograde labeling of neurons via viral infection at their terminals allows the neurons to be manipulated on the basis of their projections. However, current viral tools have disadvantages such as neurotoxicity and limited tropism. CAV-2 (canine adenovirus type 2) is a good example: this benign virus has been used for retrograde labeling but can infect only a narrow range of neurons. Li et al. have now overcome CAV-2’s limited tropism by establishing a complementation strategy. They transduce cells of interest with an adeno-associated virus (AAV) vector that delivers a receptor called CAR, which is recognized by CAV-2 and facilitates its uptake. CAV-2 can then deliver Cre to the cells, leading to the expression of Cre-dependent effector genes. Furthermore, Li et al. generated a suite of AAV vectors that encode Cre-dependent effectors such as fluorescent proteins, calcium sensors or channelrhodopsin. This strategy allowed the researchers to label projection neurons that have not been amenable to retrograde targeting. The approach also works in rats.