Pre-post synaptic alignment through neuroligin-1 tunes synaptic transmission efficiency
- Université de Bordeaux, France
- Howard Hughes Medical Institute, Salk Institute for Biological Studies, United States
Abstract
The nanoscale organization of neurotransmitter receptors regarding pre-synaptic release sites is a fundamental determinant of the synaptic transmission amplitude and reliability. How modifications in the pre- and post-synaptic machineries alignment affects synaptic currents, has only been addressed with computer modelling. Using single molecule super-resolution microscopy, we found a strong spatial correlation between AMPA receptor (AMPAR) nanodomains and the post-synaptic adhesion protein neuroligin-1 (NLG1). Expression of a truncated form of NLG1 disrupted this correlation without affecting the intrinsic AMPAR organization, shifting the pre-synaptic release machinery away from AMPAR nanodomains. Electrophysiology in dissociated and organotypic hippocampal rodent cultures shows these treatments significantly decrease AMPAR-mediated miniature and EPSC amplitudes. Computer modelling predicts that ~100nm lateral shift between AMPAR nanoclusters and glutamate release sites induces a significant reduction in AMPAR-mediated currents. Thus, our results suggest the synapses necessity to release glutamate precisely in front of AMPAR nanodomains, to maintain a high synaptic responses efficiency.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Dolors Grillo-Bosch
Terrence J Sejnowski
Funding
Agence Nationale de la Recherche (NanoDom)
- Mathieu Letellier
- Daniel Choquet
- Olivier Thoumine
- Eric Hosy
Centre National de la Recherche Scientifique
- Mathieu Letellier
- Matthieu Sainlos
- Daniel Choquet
- Olivier Thoumine
- Eric Hosy
Fondation pour la Recherche Médicale
- Benjamin Compans
H2020 European Research Council (nano-dyn-syn)
- Kalina T Haas
- Benjamin Compans
- Dolors Grillo-Bosch
- Matthieu Sainlos
- Daniel Choquet
- Eric Hosy
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: These experiments have been conducted in France, the rat Ratus norvegicus, in accordance with directive 86/609/EEC of 19 October 1986, on the protection of animals used for experimental and other scientific purposes. It was followed in France by 3 rulings in 1987, 2001, 2005 (article R214-87 and R214-130 of the rural code) and 3 rulings of 19 April 1988. An ethical system complemented this regulation since 2008, with harmonization of the commitments between the private and the public sector, by the signature of the National Charter for ethical animal experimentation by institutions in animal experimentation ethics (EAA) and by the CNREEA (Centre national of ethical reflection on animal experiments). Our projects are therefore assessed by the Ethics Committee No 50 of Bordeaux attached to the CNREEA. Thanks to our preparation, we will be ready to apply from January 1St, 2013, the 63-2010-EU directive which transcribed in French law will be published on November 12, 2012 in the form of 2 decree (Code Rural R214-87 to 138) and 4 bylaws.
Copyright
© 2018, Haas et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Pre-post synaptic alignment through neuroligin-1 tunes synaptic transmission efficiency
eLife 7:e31755.
https://doi.org/10.7554/eLife.31755
Further reading
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Early-life stress can have lifelong consequences, enhancing stress susceptibility and resulting in behavioural and cognitive deficits. While the effects of early-life stress on neuronal function have been well-described, we still know very little about the contribution of non-neuronal brain cells. Investigating the complex interactions between distinct brain cell types is critical to fully understand how cellular changes manifest as behavioural deficits following early-life stress. Here, using male and female mice we report that early-life stress induces anxiety-like behaviour and fear generalisation in an amygdala-dependent learning and memory task. These behavioural changes were associated with impaired synaptic plasticity, increased neural excitability, and astrocyte hypofunction. Genetic perturbation of amygdala astrocyte function by either reducing astrocyte calcium activity or reducing astrocyte network function was sufficient to replicate cellular, synaptic, and fear memory generalisation associated with early-life stress. Our data reveal a role of astrocytes in tuning emotionally salient memory and provide mechanistic links between early-life stress, astrocyte hypofunction, and behavioural deficits.
