Rapid Vesicular Release, Quantal Variability, and Spillover Contribute to the Precision and Reliability of Transmission at a Glomerular Synapse

Abstract

The amplitude and shape of EPSC waveforms are thought to be important determinants of information processing and storage in the brain, yet relatively little is known about the origins of EPSC variability or how it affects synaptic signaling. We investigated the stochastic determinants of AMPA receptor-mediated EPSC variability at cerebellar mossy fiber-granule cell (MF-GC) connections by combining multiple-probability fluctuation analysis (MPFA) and deconvolution methods. The properties of MF connections with a single release site and the effects of the rapidly equilibrating competitive antagonist kynurenic acid on EPSCs suggest that receptors are not saturated by glutamate during a quantal event and that quanta sum linearly over a wide range of release probabilities. MPFA revealed an average of five vesicular release sites per MF-GC connection. Our results show that the time course of vesicular release is rapid (decay, ϭ 75 s) and independent of release probability, introducing little jitter in the shape or timing of the quantal component of the EPSC at physiological temperature. Moreover, the peak vesicular release rate per release site after an action potential (AP) (ϳ3 ms Ϫ1 ) is substantially higher than previously reported for central synapses. Interaction of amplitude fluctuations arising from quantal release and quantal size with the slower, low variability spillover-mediated current produce substantial variability in EPSC shape. Our simulations of MF-GC transmission suggest that quantal variability and transmitter spillover extend the voltage from which AP threshold can be crossed, improving reliability, and that fast vesicular release allows precise signaling across MF connections with heterogeneous weights.

Heterosynaptic GABAergic plasticity bidirectionally driven by the activity of pre- and postsynaptic NMDA receptors

“…The GoC-mediated inhibition is a fundamental player in controlling the temporal coding in cerebellar circuitry. GoC inhibition was in fact shown to operate as gain controller of GrC excitation and regulator of the temporal fidelity of mf-GrC neurotransmission (11,15,17,35).…”

Distinctive Quantal Properties of Neurotransmission at Excitatory and Inhibitory Autapses Revealed Using Variance–Mean Analysis

“…V-M analysis is increasingly more popular than classical histogram-based quantal analysis as a means of characterizing synaptic function (Silver et al, 1998;Reid and Clements, 1999;Oleskevich et al, 2000;Oleskevich and Walmsley, 2002;Foster and Regehr, 2004;Sargent et al, 2005;Biró et al, 2006;Zhang et al, 2006;Baldelli et al, 2007). A major advantage of the V-M approach, at least in its simple form, is that estimates of N and Q can be obtained relatively easily, without the complex and error-prone histogram-fitting procedure of classical quantal analysis (Stricker and Redman, 2003;Ninio, 2007).…”

“…This technique is appealing because, in its simplest form, it is easier to apply than the traditional, histogram-based quantal analysis (Stricker and Redman, 2003). Thus, the V-M approach has increasingly been used to assess functional changes at synapses (Oleskevich et al, 2000;Foster and Regehr, 2004;Sargent et al, 2005;Biró et al, 2006;Zhang et al, 2006;Baldelli et al, 2007). However, despite its growing popularity, the V-M technique has not yet been empirically verified in a system that previously has been well characterized using other methods of quantal analysis.…”

“…A second characteristic of the V-M approach is that, to date, it has been applied largely to excitatory, glutamate-releasing synapses (e.g., Biró et al, 2005;Sargent et al, 2005;Tyler et al, 2006) (cf. Biró et al, 2006).…”

Multivesicular Release at Schaffer Collateral–CA1 Hippocampal Synapses

“…At many central synapses, however, release caused by a single presynaptic action potential is limited to one vesicle [univesicular release (UVR)] (Gulyás et al, 1993;Lawrence et al, 2003;Silver et al, 2003;Murphy et al, 2004;Biró et al, 2005;Sargent et al, 2005). Thus far, unifying or predictive characteristics of these synapses have not emerged.…”