Abstract
Action potentials trigger two modes of neurotransmitter release, with a fast synchronous component and a temporally delayed asynchronous release. Asynchronous release contributes to information transfer at synapses, including at the hippocampal mossy fiber (MF) to CA3 pyramidal cell synapse where it controls the timing of postsynaptic CA3 pyramidal neuron firing. Here, we identified and characterized the main determinants of asynchronous release at the MF–CA3 synapse. We found that asynchronous release at MF–CA3 synapses can last on the order of seconds following repetitive MF stimulation. Elevating the stimulation frequency or the external Ca2+ concentration increased the rate of asynchronous release, thus, arguing that presynaptic Ca2+ dynamics is the major determinant of asynchronous release rate. Direct MF bouton Ca2+ imaging revealed slow Ca2+ decay kinetics of action potential (AP) burst‐evoked Ca2+ transients. Finally, we observed that asynchronous release was preferentially mediated by Ca2+ influx through P/Q‐type voltage‐gated Ca2+ channels, while the contribution of N‐type VGCCs was limited. Overall, our results uncover the determinants of long‐lasting asynchronous release from MF terminals and suggest that asynchronous release could influence CA3 pyramidal cell firing up to seconds following termination of granule cell bursting.
Highlights
Neurotransmitter release from presynaptic terminals occurs in different modes following action potential firing
Our results show that atypical slowly decaying presynaptic Ca2+ elevations in mossy fiber (MF) presynaptic terminals contribute to long-lasting asynchronous release following termination of granule cell firing
Asynchronous release has been shown to co-occur with synchronous release at multiple synapses, and there is general agreement that asynchronous release increases with the level of activity (Atluri & Regehr, 1998)
Summary
Iremonger & Bains, 2007). Synchronous release is precisely timed to the action potential-induced Ca2+ influx, while asynchronous release is temporally delayed, and can last for hundreds of milliseconds following stimulus termination (Barrett & Stevens, 1972; Daw, Tricoire, Erdelyi, Szabo, & McBain, 2009; Hefft & Jonas, 2005). Synchronous and asynchronous release co-occur in presynaptic terminals, including from MFBs (Evstratova et al, 2014) It remains unknown whether different patterns of activity selectively recruit distinct modes of release and how the stimulation frequency modulates asynchronous release from MFBs. We recorded trains of MF–EPSCs evoked by 10 stimuli at 10, 20, 50, or 100 Hz (Figure 2a-b) in artificial cerebrospinal fluid (ACSF) containing 2.5 mM Ca2+. This result argues that the slowly decaying Ca2+ elevations in giant MF boutons could represent a mechanism for the generation and maintenance of long-lasting asynchronous release. These results suggest that asynchronous release is initially decreased but prolonged, such that the total asynchronous release observed over 10 s is similar as in control
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