In most neurons, the axon derives from the somatic compartment, giving equal weight to signals from all dendritic processes. We determined the origin of the axon in hippocampal pyramidal cells, using immunolabeling of the axon initial segment in mice with sparsely dsRed labeled principal neurons. Surprisingly, in a large fraction of pyramidal neurons the axon originated from a basal dendrite at varying distances to the soma. This cellular morphology was particularly enriched in CA1 (about 50%), but was also found in CA3 and the subiculum.
The initial segment of the axon is thought to be the actual site for action potential generation and thus central for neuronal output. We therefore investigated whether axon-carrying dendrites (AcDs) convey privileged input due to their particular proximity to the axon initial segment. Using combined patch-clamp recordings and two-photon glutamate uncaging, we demonstrated that AcDs are intrinsically more excitable than regular dendrites, generating dendritic spikes with higher probability and greater strength. Furthermore, action potentials generated by inputs to AcDs had a lower threshold compared to those triggered from simple dendrites. Computational modeling studies revealed that the increased efficacy of AcDs can be explained by the smaller electrotonic distance between synaptic input to AcD branches and the axon initial segment. Our findings indicate that AcDs are privileged channels for excitatory synaptic input to hippocampal pyramidal neurons, revealing a fundamental morphological and functional asymmetry of synaptic signal integration.