Release Probability-Dependent Scaling of the Postsynaptic Responses at Single Hippocampal GABAergic Synapses

Abstract

The amount of neurotransmitter released after the arrival of an action potential affects the strength and the trial-to-trial variability of postsynaptic responses. Most studies examining the dependence of synaptic neurotransmitter concentration on the release probability (P r ) have focused on glutamatergic synapses. Here we asked whether univesicular or multivesicular release characterizes transmission at hippocampal GABAergic synapses. We used multiple probability functional analysis to derive quantal parameters at inhibitory connections between cannabinoid receptor-and cholecystokinin (CCK)-expressing interneurons and CA3 pyramidal cells. After the recordings, the cells were visualized and reconstructed at the light-microscopic level, and the number of boutons mediating the IPSCs was determined using electron microscopy (EM). The number of active zones (AZs) per CCK-immunopositive bouton was determined from threedimensional EM reconstructions, thus allowing the calculation of the total number of AZs for each pair. Our results reveal an approximate fivefold discrepancy between the numbers of functionally determined release sites (17.4 Ϯ 3.2) and structurally identified AZs (3.7 Ϯ 0.9). Channel modeling predicts that a fivefold to sevenfold increase in the peak synaptic GABA concentration is required for the fivefold enhancement of the postsynaptic responses. Kinetic analysis of the unitary IPSCs indicates that the increase in synaptic GABA concentration is most likely attributable to multivesicular release. This change in the synaptic GABA concentration transient together with extremely low postsynaptic receptor occupancy permits a P r -dependent scaling of the postsynaptic response generated at a single hippocampal GABAergic synaptic contact.

Inhibitory Synapse Dynamics: Coordinated Presynaptic and Postsynaptic Mobility and the Major Contribution of Recycled Vesicles to New Synapse Formation

“…5C) may indicate flux in postsynaptic elements on a single dendrite region associated with a multiple synapse bouton. GABAergic boutons bearing multiple active zones, each with associated postsynaptic specialization, have been described previously in several brain regions (Studler et al, 2002;Biro et al, 2006). At such GABAergic synapses, spillover of transmitter released from one active zone may activate receptors opposite another active zone and may contribute to high persistent inhibition over stimulus trains (Telgkamp et al, 2004;Wanaverbecq et al, 2008).…”

Dopaminergic modulation of short-term synaptic plasticity at striatal inhibitory synapses

“…5A) (4,8,48). However, as in other cases, intrinsic quantal variability associated with unitary connections, and other factors, impeded a precise distinction between N (release sites) and P (release probability) (41,51). However, both parameters signal presynaptic mechanisms.…”

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.…”

“…Biró et al, 2006). Previous work, using various techniques, has indicated that synapses releasing the inhibitory neurotransmitter GABA cannot simply be assumed to exhibit quantal properties identical to those of excitatory synapses (Fedulova et al, 1999;Gitler et al, 2004;Sakaba, 2008).…”