Unveiling the cell biology of hippocampal neurons with dendritic axon origin

In mammalian axon-carrying-dendrite (AcD) neurons, the axon emanates from a basal dendrite, instead of the soma, to create a privileged route for action potential generation at the axon initial segment (AIS). However, it is unclear how such unusual morphology is established and whether the structure and function of the AIS in AcD neurons is preserved. Here, we show that the AcD neurons follow an intrinsically encoded developmental program where a single precursor neurite first gives rise to the axon and then to the AcD. The AIS possesses a similar cytoskeletal architecture as the canonical AIS that stems from the soma, and similarly functions as a trafficking barrier to retain axon-specific molecular composition. However, unlike soma-derived AIS, the AIS of AcD neurons does not undergo homeostatic-plasticity, contains less cisternal organelles and receives fewer inhibitory inputs. These distinct features of the AIS could account for the higher intrinsic excitability of AcD neurons.