| Factors affecting action potential conduction, vesicle availability, and release probability help shape synaptic transmission. Plasticity of synaptic transmission during physiologically relevant repetitive stimulation is thus reflective of these underlying neuronal processes and mechanisms. The goal of this work is to develop better understanding of the determinants of synaptic transmission, with a specific focus on the mechanisms underlying synaptic depression during stimulus trains.; Hippocampal neurons grown in culture were stimulated with pulse trains of varying length. Three phases of pulse train depression were identified. Our results suggest the following model. The initial phase of depression, evident after a single stimulus, is caused by depletion of an immediately releasable pool (IRP) of vesicles. An intermediate phase of depression results from additional depletion of the IRP due to a build up of asynchronous release. Finally, a late phase of depression, occurring within a few hundred pulses, is due to action potential (AP) conduction failure.; Our results indicate that the IRP, representing the most release-ready of the docked synaptic vesicles, is limited to, at most, one vesicle per synapse. This contrasts with the conventional view that all of the docked vesicles of the readily releasable pool (RRP) are equally ready for release. We also find that synchronous and asynchronous release both share and are limited to the IRP; this is an important, previously unrecognized insight about the relationship between these two forms of release. Finally, evidence of AP conduction failure raises serious questions about the fidelity of transmission during prolonged pulse trains. These results have important implications for the interpretation of experimental results derived from the use of repetitive pulse trains, as well as for the future study of underlying molecular processes. |
