LAUSR

Significance Neurons have an exceptional capacity to grow axons and form synaptic circuits during development but not later life. In adults, the lack of circuit formation may support retention of skilled actions and memories but also limits regeneration and repair after injuries and in disorders. Research on developing and damaged neurons has revealed many molecules that help circuit formation and regeneration, and yet factors that could induce axon growth and synapse formation in adult brain neurons remain elusive. Here, we searched for such key molecules and find one that alone can induce complete circuit formation. After engineering a new circuit in adult mice, we also looked into its function and relevance for memories. Circuit formation in the central nervous system has been historically studied during development, after which cell-autonomous and nonautonomous wiring factors inactivate. In principle, balanced reactivation of such factors could enable further wiring in adults, but their relative contributions may be circuit dependent and are largely unknown. Here, we investigated hippocampal mossy fiber sprouting to gain insight into wiring mechanisms in mature circuits. We found that sole ectopic expression of Id2 in granule cells is capable of driving mossy fiber sprouting in healthy adult mouse and rat. Mice with the new mossy fiber circuit solved spatial problems equally well as controls but appeared to rely on local rather than global spatial cues. Our results demonstrate reprogrammed connectivity in mature neurons by one defined factor and an assembly of a new synaptic circuit in adult brain.