Neuregulin 3 promotes excitatory synapse formation on hippocampal interneurons

Hippocampal GABAergic interneurons are crucial for cortical network function and have been implicated in psychiatric disorders. We show here that Neuregulin 3 (Nrg3), a relatively little investigated low‐affinity ligand, is a functionally dominant interaction partner of ErbB4 in parvalbumin‐positive (PV) interneurons. Nrg3 and ErbB4 are located pre‐ and postsynaptically, respectively, in excitatory synapses on PV interneurons in vivo . Additionally, we show that ablation of Nrg3 results in a similar phenotype as the one described for ErbB4 ablation, including reduced excitatory synapse numbers on PV interneurons, altered short‐term plasticity, and disinhibition of the hippocampal network. In culture, presynaptic Nrg3 increases excitatory synapse numbers on ErbB4 + interneurons and affects short‐term plasticity. Nrg3 mutant neurons are poor donors of presynaptic terminals in the presence of competing neurons that produce recombinant Nrg3, and this bias requires postsynaptic ErbB4 but not ErbB4 kinase activity. Furthermore, when presented by non‐neuronal cells, Nrg3 induces postsynaptic membrane specialization. Our data indicate that Nrg3 provides adhesive cues that facilitate excitatory neurons to synapse onto ErbB4 + interneurons. Synopsis Nrg3 is a low affinity ligand of the ErbB4 tyrosine kinase receptor that has poor signaling activity. Nrg3/ErbB4 interactions provide adhesive cues that promote formation and function of excitatory synapses onto ErbB4 + inhibitory neurons. Nrg3 promotes formation and maturation of excitatory synapses onto ErbB4 + interneurons in the hippocampus. Nrg3 presented by non‐neuronal cells induces postsynaptic membrane specialization in ErbB4 + interneurons. Nrg3 provides adhesive cues that facilitate excitatory neurons to synapse onto ErbB4 + interneurons. Nrg3 is an important ErbB4 interaction partner for synaptogenesis and synapse function. Graphical Abstract Neuregulin 3 and its receptor the tyrosine kinase ErbB4 promote synaptic adhesion to facilitate synaptogenesis and synapse function.