Axons are generally considered as reliable transmission cables in which stable propagation occurs once an action potential is generated. Axon dysfunction occupies a central position in many inherited and acquired neurological disorders that affect both peripheral and central neurons. Recent findings suggest that the functional and computational repertoire of the axon is much richer than traditionally thought. Beyond classical axonal propagation, intrinsic voltage-gated ionic currents together with the geometrical properties of the axon determine several complex operations that not only control signal processing in brain circuits but also neuronal timing and synaptic efficacy. Recent evidence for the implication of these forms of axonal computation in the short-term dynamics of neuronal communication is discussed. Finally, we review how neuronal activity regulates both axon morphology and axonal function on a long-term time scale during development and adulthood.

Acidification of synaptic vesicles by the vacuolar proton ATPase is essential for loading with neurotransmitter. Debated findings have suggested that V-ATPase membrane domain (V0) also contributes to Ca(2+)-dependent transmitter release via a direct role in vesicle membrane fusion, but the underlying mechanisms remain obscure. We now report a direct interaction between V0 c-subunit and the v-SNARE synaptobrevin, constituting a molecular link between the V-ATPase and SNARE-mediated fusion. Interaction domains were mapped to the membrane-proximal domain of VAMP2 and the cytosolic 3.4 loop of c-subunit. Acute perturbation of this interaction with c-subunit 3.4 loop peptides did not affect synaptic vesicle proton pump activity, but induced a substantial decrease in neurotransmitter release probability, inhibiting glutamatergic as well as cholinergic transmission in cortical slices and cultured sympathetic neurons, respectively. Thus, V-ATPase may ensure two independent functions: proton transport by a fully assembled V-ATPase and a role in SNARE-dependent exocytosis by the V0 sector.

In the mammalian brain, synaptic transmission usually depends on presynaptic action potentials (APs) in an all-or-none (or digital) manner. Recent studies suggest, however, that subthreshold depolarization in the presynaptic cell facilitates spike-evoked transmission, thus creating an analogue modulation of a digital process (or analogue–digital (AD) modulation). At most synapses, this process is slow and not ideally suited for the fast dynamics of neural networks. We show here that transmission at CA3–CA3 and L5–L5 synapses can be enhanced by brief presynaptic hyperpolarization such as an inhibitory postsynaptic potential (IPSP). Using dual soma–axon patch recordings and live imaging, we find that this hyperpolarization-induced AD facilitation (h-ADF) is due to the recovery from inactivation of Nav channels controlling AP amplitude in the axon. Incorporated in a network model, h-ADF promotes both pyramidal cell synchrony and gamma oscillations. In conclusion, cortical excitatory synapses in local circuits display hyperpolarization-induced facilitation of spike-evoked synaptic transmission that promotes network synchrony.