Reciprocal repulsions instruct the precise assembly ofparallel hippocampal networks

Abstract

Parallel information processing is a salient feature of complex nervous systems. For example, the medial and lateral hippocampal networks (MHN and LHN) preferentially process spatial- and object-related information, respectively. However, the mechanisms underlying parallel network assembly during development remain largely unknown. Here, we show that complementary expression of cell-surface molecules Teneurin-3 (Ten3) and Latrophilin-2 (Lphn2) in the MHN and LHN, respectively, guides the precise assembly of both the MHN and LHN. Viral-genetic perturbations in vivo demonstrate that Ten3+ axons are repelled by target-derived Lphn2, revealing that Lphn2/Ten3-mediated repulsion and Ten3/Ten3-mediated attraction cooperate to control precise target selection of MHN axons. In the LHN, Lphn2+ axons are confined to Lphn2+ targets via repulsion from Ten3+ targets. Our findings demonstrate that assembly of parallel hippocampal networks follows a Ten3[->]Ten3, Lphn2[->]Lphn2 rule instructed by reciprocal repulsions.