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Estimation of the time course of neurotransmitter release at central synapses from the first latency of postsynaptic currents

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      Highlights

      ► Method for estimating vesicular release time course from PSC first latencies. ► Analytical derivation of binomial model of release at central synapses. ► Systematic tests of robustness with biologically realistic simulations. ► Generalization of existing first latency correction based on Poisson model.

      Abstract

      Measurement of the release time course (RTC) and of the quantal content is important for quantifying synaptic precision and understanding the molecular basis of the release process at central synapses. In theory, the RTC can be determined directly from the histogram of first latencies of quantal events only if a maximum of one vesicle is released per trial, but at most synapses multiple vesicles are released. Traditionally, first latency histograms have been corrected for multiple releases using a simple correction, derived by Barrett and Stevens (BS; 1972b) for quantifying release at the neuromuscular junction. This correction has also been used to quantify release at central synapses. We show, by combining an analytical approach and numerical simulations of stochastic quantal release, that the BS correction gives a biased estimate for RTC and quantal content. The bias increases with release probability, and is therefore particularly problematic for central synapses. We show that this is due to assuming infinite availability of releasable vesicles and we derive a formula for estimating the RTC from first latencies without this assumption. The resulting ‘binomial correction’ requires knowledge of the maximum number of quanta that can be released following an action potential ( N), which can be estimated with variance-mean analysis. We show with simulations that estimating RTC and quantal content from first latencies using the binomial correction is robust in the presence of noise and when release probability is non-uniform. We also provide an alternative method for estimating RTC from the first latencies when N cannot be determined.

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      Most cited references 56

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      Heterogeneity of release probability, facilitation, and depletion at central synapses.

      Previous studies of short-term plasticity in central nervous systems synapses have largely focused on average synaptic properties. In this study, we use recordings from putative single synaptic release sites in hippocampal slices to show that significant heterogeneity exists in facilitation and depletion among synapses. In particular, the amount of paired-pulse facilitation is inversely related to the initial release probability of the synapse. We also examined depletion at individual synapses using high frequency stimulation, and estimated the size of the readily releasable vesicle pool, which averaged 5.0 +/- 3.0 quanta (n = 13 synapses). In addition, these experiments demonstrate that the release probability at a synapse is directly correlated with the size of its readily releasable vesicle pool.
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        Synaptic vesicle pools.

        Communication between cells reaches its highest degree of specialization at chemical synapses. Some synapses talk in a 'whisper'; others 'shout'. The 'louder' the synapse, the more synaptic vesicles are needed to maintain effective transmission, ranging from a few hundred (whisperers) to nearly a million (shouters). These vesicles reside in different 'pools', which have been given a bewildering array of names. In this review, we focus on five tissue preparations in which synaptic vesicle pools have been identified and thoroughly characterized. We argue that, in each preparation, each vesicle can be assigned to one of three distinct pools.
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          Quantal components of the end-plate potential.

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            Author and article information

            Affiliations
            Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK
            Author notes
            [* ]Corresponding author. Tel.: +44 0 20 7679 7830. a.silver@ 123456ucl.ac.uk
            Contributors
            Journal
            J Neurosci Methods
            J. Neurosci. Methods
            Journal of Neuroscience Methods
            Elsevier/North-Holland Biomedical Press
            0165-0270
            1872-678X
            30 March 2012
            30 March 2012
            : 205
            : 1-2
            : 49-64
            3314961
            22226741
            NSM6241
            10.1016/j.jneumeth.2011.12.015
            © 2012 Elsevier B.V.

            This document may be redistributed and reused, subject to certain conditions.

            Categories
            Basic Neuroscience

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