title: Activity-dependent changes in temporal components of neurotransmission at the juvenile mouse calyx of Held synapse.
abstract: The temporal fidelity of synaptic transmission is constrained by the reproducibility of time delays such as axonal conduction delay and synaptic delay, but very little is known about the modulation of these distinct components. In particular, synaptic delay is not generally considered to be modifiable under physiological conditions. Using simultaneous paired patch-clamp recordings from pre- and postsynaptic elements of the calyx of Held synapse, in juvenile mouse auditory brainstem slices, we show here that synaptic activity (20-200 Hz) leads to activity-dependent increases in synaptic delay and its variance as well as desynchronization of evoked responses. Such changes were most robust at 200 Hz in 2 mM extracellular Ca(2+) ([Ca(2+)](o)), and could be attenuated by lowering [Ca(2+)](o) to 1 mM, increasing temperature to 35 degrees C, or application of the GABA(B)R agonist baclofen, which inhibits presynaptic Ca(2+) currents (I(Ca)). Conduction delay also exhibited slight activity-dependent prolongation, but this prolongation was only sensitive to temperature, and not to [Ca(2+)](o) or baclofen. Direct voltage-clamp recordings of I(Ca) evoked by repeated action potential train template (200 Hz) revealed little jitter in the timing and kinetics of I(Ca) under various conditions, suggesting that increases in synaptic delay and its variance occur downstream of Ca(2+) entry. Loading the Ca(2+) chelator EGTA-AM into terminals reduced the progression rate, the extent of activity-dependent increases in various delay components, and their variance, implying that residual Ca(2+) accumulation in the presynaptic nerve terminal induces these changes. Finally, by applying a test pulse at different intervals following a 200 Hz train (150 ms), we demonstrated that prolongation in the various delay components reverses in parallel with recovery in synaptic strength. These observations suggest that a depletion of the readily releasable pool of SVs during high-frequency activity may downregulate not only synaptic strength but also decrease the temporal fidelity of neurotransmission at this and other central synapses.
authors.affiliation: Division of Neurology, The Hospital for Sick Children, Department of Physiology, University of Toronto, 555 University Avenue, Toronto, Ontario, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fedchyshyn
authors.forename: Lu-Yang
authors.initials: LY
authors.lastname: Wang
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D017626:Cochlear Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D016057:Evoked Potentials, Auditory, Brain Stem; D018755:GABA Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009431:Neural Conduction / Q000502:physiology; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D015203:Reproducibility of Results; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism*; D013696:Temperature
chemical_list: D002614:Chelating Agents; D018755:GABA Agonists; D004533:Egtazic Acid; C046770:EGTA acetoxymethyl ester; D001418:Baclofen; D002118:Calcium