Fully-primed slowly-recovering vesicles mediate presynaptic LTP at neocortical neurons

Author:

Weichard Iron1,Taschenberger Holger2ORCID,Gsell Felix1,Bornschein Grit1ORCID,Ritzau-Jost Andreas1,Schmidt Hartmut1ORCID,Kittel Robert J.3ORCID,Eilers Jens1ORCID,Neher Erwin45ORCID,Hallermann Stefan1ORCID,Nerlich Jana1ORCID

Affiliation:

1. Faculty of Medicine, Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig 04103, Germany

2. Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Göttingen 37075, Germany

3. Department of Animal Physiology, Institute of Biology, Leipzig University, Leipzig 04103, Germany

4. Emeritus Laboratory of Membrane Biophysics, Max Planck Institute for Multidisciplinary Sciences, Göttingen 37070, Germany

5. Cluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells”, University of Göttingen, Göttingen 37073, Germany

Abstract

Pre- and postsynaptic forms of long-term potentiation (LTP) are candidate synaptic mechanisms underlying learning and memory. At layer 5 pyramidal neurons, LTP increases the initial synaptic strength but also short-term depression during high-frequency transmission. This classical form of presynaptic LTP has been referred to as redistribution of synaptic efficacy. However, the underlying mechanisms remain unclear. We therefore performed whole-cell recordings from layer 5 pyramidal neurons in acute cortical slices of rats and analyzed presynaptic function before and after LTP induction by paired pre- and postsynaptic neuronal activity. LTP was successfully induced in about half of the synaptic connections tested and resulted in increased synaptic short-term depression during high-frequency transmission and a decelerated recovery from short-term depression due to an increased fraction of a slow recovery component. Analysis with a recently established sequential two-step vesicle priming model indicates an increase in the abundance of fully-primed and slowly-recovering vesicles. A systematic analysis of short-term plasticity and synapse-to-synapse variability of synaptic strength at various types of synapses revealed that stronger synapses generally recover more slowly from synaptic short-term depression. Finally, pharmacological stimulation of the cyclic adenosine monophosphate and diacylglycerol signaling pathways, which are both known to promote synaptic vesicle priming, mimicked LTP and slowed the recovery from short-term depression. Our data thus demonstrate that LTP at layer 5 pyramidal neurons increases synaptic strength primarily by enlarging a subpool of fully-primed slowly-recovering vesicles.

Funder

Deutsche Forschungsgemeinschaft

EC | European Research Council Consolidator Grant

Deutsche Forschungsgemeinschaft (DFG) under Germany's Excellence Strategy

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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