Teneurin-3 controls topographic circuit assembly in the hippocampus

Brain functions rely on specific patterns of connectivity. Teneurins are evolutionarily conserved transmembrane proteins that instruct synaptic partner matching in Drosophila and are required for vertebrate visual system development. The roles of vertebrate teneurins in connectivity beyond the visual system remain largely unknown and their mechanisms of action have not been demonstrated. Here we show that mouse teneurin-3 is expressed in multiple topographically interconnected areas of the hippocampal region, including proximal CA1, distal subiculum, and medial entorhinal cortex. Viral-genetic analyses reveal that teneurin-3 is required in both CA1 and subicular neurons for the precise targeting of proximal CA1 axons to distal subiculum. Furthermore, teneurin-3 promotes homophilic adhesion in vitro in a splicing isoform-dependent manner. These findings demonstrate striking genetic heterogeneity across multiple hippocampal areas and suggest that teneurin-3 may orchestrate the assembly of a complex distributed circuit in the mammalian brain via matching expression and homophilic attraction. The transmembrane protein teneurin-3 is expressed in multiple topographically interconnected areas of the hippocampal region and acts in both projection and target neurons to control wiring specificity from CA1 to the subiculum. Wiring the mammalian brain Teneurins are large transmembrane proteins that contribute to correct brain circuit wiring in Drosophila , but beyond their contribution to the visual system their role in the developing brain of mammals is not known. Here, Liqun Luo and colleagues demonstrate the necessity for teneurin-3 in the proper wiring of the hippocampus in mice. Teneurin-3 isoforms bind with homophilic attraction, which enables this single protein to assemble complex circuits like those in the hippocampus precisely through various distributed spliced variants.