Model of subcellular NRG3 trafficking in central neurons. Schematic diagram depicting the intricate interplay between NRG3 proteolytic processing, transcytosis, and ErbB4-dependent retention that result in the presynaptic accumulation of NRG3 at glutamatergic synapses onto ErbB4+ GABAergic interneurons. The process begins in the TGN where unprocessed proNRG3 is cleaved by BACE1 to separate its constituent NTF (green) and CTF (red) moieties (inset 1). Next, the NRG3 NTF trafficks to the somatodendritic cell surface from where it is re-internalized, likely via clathrin-dependent endocytosis based on data obtained with the inhibitor Pitstop (see Fig. 4), into Rab5+ endosomes (inset 2). It is then sorted into Rab4+ vesicles and anterogradely transported into axons, likely by moving on microtubule tracks via kinesin motors. Finally, the NRG3 NTF re-emerges on the axonal cell surface and is retained at presynaptic terminals by trans-synaptic interaction with ErbB4 receptors concentrated at postsynaptic densities of glutamatergic synapses (inset 3). Although trafficking of the CTF following BACE1 cleavage was not explored in this study, low CTF-only signals suggest quick turnover, possibly by lysosomal degradation (although other functions are conceivable). See main text for further discussion.