Excitatory synapses onto axonic spines jump-start action potentials and route information flow

Synaptic inputs onto the dendrites and cell body integrate and trigger action potentials (APs) at the axon initial segment (AIS). The AIS receives GABAergic synaptic inputs; however, the structure and function of glutamatergic synapses at the AIS remain poorly understood. Here, we show that, in adult mice, the AIS exhibits axonic spines in about half of the neurons examined in three brain regions: the dorsal lateral septum (dLS), bed nucleus of the stria terminalis and striatum. In the dLS, axonic spines express ionotropic glutamate receptors and undergo structural plasticity. Voltage-gated Na⁺ channels at the AIS boost the synaptic responses of axonic spines and thus AP generation. Although hippocampal dorsal CA3 neurons synapse onto both axonic spine neurons (ASNs) and non-ASNs, they preferentially activate ASNs and subsequently inhibit non-ASNs through feedforward inhibition. Together, these results indicate that axonic spines jump-start APs in dLS neurons and route information flow from the hippocampus to downstream brain regions.