Variability in the Munc13-1 content of excitatory release sites.

Maria Rita Karlocai,Judit Heredi,Andrea Lorincz,Tünde Benedek,Zoltan Nusser,Noemi Holderith

doi:10.7554/elife.67468

Abstract

The molecular mechanisms underlying the diversity of cortical glutamatergic synapses are still incompletely understood. Here, we tested the hypothesis that presynaptic active zones (AZs) are constructed from molecularly uniform, independent release sites (RSs), the number of which scales linearly with the AZ size. Paired recordings between hippocampal CA1 pyramidal cells and fast-spiking interneurons in acute slices from adult mice followed by quantal analysis demonstrate large variability in the number of RSs (N) at these connections. High-resolution molecular analysis of functionally characterized synapses reveals variability in the content of one of the key vesicle priming factors - Munc13-1 - in AZs that possess the same N. Replica immunolabeling also shows a threefold variability in the total Munc13-1 content of AZs of identical size and a fourfold variability in the size and density of Munc13-1 clusters within the AZs. Our results provide evidence for quantitative molecular heterogeneity of RSs and support a model in which the AZ is built up from variable numbers of molecularly heterogeneous, but independent RSs.

Highlights

Computational complexity of neuronal networks is greatly enhanced by the diversity in synaptic function (Dittman et al, 2000; O’Rourke et al, 2012)
Large variability in unitary EPSC amplitudes evoked by CA1 pyramidal cells (PCs) in fast-spiking interneurons (FSINs)
To investigate the variance in unitary EPSC amplitudes evoked in FSINs by CA1 PC single action potentials (APs), we recorded a total of 79 monosynaptically connected pairs in 2 mM external [Ca2+] from acute slices of adult mice of both sexes (Figure 1)

Summary

Introduction

Computational complexity of neuronal networks is greatly enhanced by the diversity in synaptic function (Dittman et al, 2000; O’Rourke et al, 2012). Robust differences in synaptic function were found when a single presynaptic cell formed synapses on different types of postsynaptic target cells. Such postsynaptic target cell type-dependent variability in vesicle release probability (Pv) and short-term plasticity was identified in cortical and hippocampal networks (Koester and Johnston, 2005; Losonczy et al, 2002; Pouille and Scanziani, 2004; Reyes et al, 1998; Rozov et al, 2001; Scanziani et al, 1998; Thomson, 1997). Studies investigating the underlying mechanisms revealed different molecules (e.g. mGluR7, kainate receptors in the AZ and Elfn in the postsynaptic density [PSD], Shigemoto et al, 1996; Sylwestrak and Ghosh, 2012), but variable densities of the same molecules were suggested as key molecular features (Eltes et al, 2017; Rozov et al, 2001)

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