Pre-post synaptic alignment through neuroligin-1 tunes synaptic transmission efficiency

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 machinery alignments 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 ~100 nm 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.

[1]  Martin Hruska,et al.  Synaptic nanomodules underlie the organization and plasticity of spine synapses , 2018, Nature Neuroscience.

[2]  Daniel Choquet,et al.  Review on the role of AMPA receptor nano-organization and dynamic in the properties of synaptic transmission , 2016, Neurophotonics.

[3]  Thomas A. Blanpied,et al.  A transsynaptic nanocolumn aligns neurotransmitter release to receptors , 2016, Nature.

[4]  O. Thoumine,et al.  Mapping the dynamics and nanoscale organization of synaptic adhesion proteins using monomeric streptavidin , 2016, Nature Communications.

[5]  T. Sejnowski,et al.  Nanoconnectomic upper bound on the variability of synaptic plasticity , 2015, eLife.

[6]  T. Sejnowski,et al.  Computational reconstitution of spine calcium transients from individual proteins , 2015, Front. Synaptic Neurosci..

[7]  Daniel Choquet,et al.  SR-Tesseler: a method to segment and quantify localization-based super-resolution microscopy data , 2015, Nature Methods.

[8]  Jonathan M Levy,et al.  Synaptic Consolidation Normalizes AMPAR Quantal Size following MAGUK Loss , 2015, Neuron.

[9]  Andreas Voigt,et al.  Mobility of Calcium Channels in the Presynaptic Membrane , 2015, Neuron.

[10]  A. Penn,et al.  Lengthening of the Stargazin Cytoplasmic Tail Increases Synaptic Transmission by Promoting Interaction to Deeper Domains of PSD-95 , 2015, Neuron.

[11]  Daniel Choquet,et al.  Glutamate-Induced AMPA Receptor Desensitization Increases Their Mobility and Modulates Short-Term Plasticity through Unbinding from Stargazin , 2015, Neuron.

[12]  E. Hosy,et al.  Organization and dynamics of AMPA receptors inside synapses-nano-organization of AMPA receptors and main synaptic scaffolding proteins revealed by super-resolution imaging. , 2014, Current opinion in chemical biology.

[13]  Daniel Choquet,et al.  Super-Resolution Imaging Reveals That AMPA Receptors Inside Synapses Are Dynamically Organized in Nanodomains Regulated by PSD95 , 2013, The Journal of Neuroscience.

[14]  F. Perez,et al.  Local palmitoylation cycles define activity-regulated postsynaptic subdomains , 2013, The Journal of cell biology.

[15]  O. Thoumine,et al.  Neurexin-1β binding to neuroligin-1 triggers the preferential recruitment of PSD-95 versus gephyrin through tyrosine phosphorylation of neuroligin-1. , 2013, Cell reports.

[16]  Yu Song,et al.  Nanoscale Scaffolding Domains within the Postsynaptic Density Concentrate Synaptic AMPA Receptors , 2013, Neuron.

[17]  Bruce H. Pillman.  Super-Resolution Imaging , 2013, J. Electronic Imaging.

[18]  Josef Spacek,et al.  Extracellular sheets and tunnels modulate glutamate diffusion in hippocampal neuropil , 2013, The Journal of comparative neurology.

[19]  Jung Hoon Jung,et al.  Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling , 2012, Proceedings of the National Academy of Sciences.

[20]  L. Savtchenko,et al.  Central Synapses Release a Resource-Efficient Amount of Glutamate , 2012, Nature Neuroscience.

[21]  B. Sabatini,et al.  Neuroligin-1–dependent competition regulates cortical synaptogenesis and synapse number , 2012, Nature Neuroscience.

[22]  B. Sabatini,et al.  Cortical synaptogenesis and excitatory synapse number are determined via a Neuroligin-1-dependent intercellular competition , 2012, Nature Neuroscience.

[23]  O. Thoumine,et al.  Unified quantitative model of AMPA receptor trafficking at synapses , 2012, Proceedings of the National Academy of Sciences.

[24]  N. Ziv,et al.  Syntaxin1A Lateral Diffusion Reveals Transient and Local SNARE Interactions , 2011, The Journal of Neuroscience.

[25]  O. Thoumine,et al.  Neurexin-Neuroligin Adhesions Capture Surface-Diffusing AMPA Receptors through PSD-95 Scaffolds , 2011, The Journal of Neuroscience.

[26]  R. Nicoll,et al.  Functional dependence of neuroligin on a new non-PDZ intracellular domain , 2011, Nature Neuroscience.

[27]  D. Rusakov,et al.  Molecular signals of plasticity at the tetrapartite synapse , 2011, Current Opinion in Neurobiology.

[28]  B. Imperiali,et al.  Biomimetic divalent ligands for the acute disruption of synaptic AMPAR stabilization. , 2011, Nature chemical biology.

[29]  Yunfeng Hua,et al.  A common origin of synaptic vesicles undergoing evoked and spontaneous fusion , 2010, Nature Neuroscience.

[30]  Silvio O Rizzoli,et al.  The same synaptic vesicles drive active and spontaneous release , 2010, Nature Neuroscience.

[31]  E. Gouaux,et al.  Dynamic superresolution imaging of endogenous proteins on living cells at ultra-high density. , 2010, Biophysical journal.

[32]  T. Südhof,et al.  Neuroligin‐1 performs neurexin‐dependent and neurexin‐independent functions in synapse validation , 2009, The EMBO journal.

[33]  Masahiko Watanabe,et al.  Input-Specific Intrasynaptic Arrangements of Ionotropic Glutamate Receptors and Their Impact on Postsynaptic Responses , 2009, The Journal of Neuroscience.

[34]  J. Burrone,et al.  A resting pool of vesicles is responsible for spontaneous vesicle fusion at the synapse , 2009, Nature Neuroscience.

[35]  R. Nicoll,et al.  Silent synapses and the emergence of a postsynaptic mechanism for LTP , 2008, Nature Reviews Neuroscience.

[36]  T. Südhof.  Neuroligins and neurexins link synaptic function to cognitive disease , 2008, Nature.

[37]  M. Heilemann,et al.  Subdiffraction-resolution fluorescence imaging with conventional fluorescent probes. , 2008, Angewandte Chemie.

[38]  Daniel Choquet,et al.  Surface Mobility of Postsynaptic AMPARs Tunes Synaptic Transmission , 2008, Science.

[39]  John E. Lisman,et al.  The sequence of events that underlie quantal transmission at central glutamatergic synapses , 2007, Nature Reviews Neuroscience.

[40]  Kazushi Fujimoto,et al.  Number and Density of AMPA Receptors in Individual Synapses in the Rat Cerebellum as Revealed by SDS-Digested Freeze-Fracture Replica Labeling , 2007, The Journal of Neuroscience.

[41]  R. Nicoll,et al.  Stargazin interacts functionally with the AMPA receptor glutamate-binding module , 2007, Neuropharmacology.

[42]  O. Prange,et al.  Neuroligins Mediate Excitatory and Inhibitory Synapse Formation , 2005, Journal of Biological Chemistry.

[43]  Lu Chen,et al.  Postsynaptic assembly induced by neurexin-neuroligin interaction and neurotransmitter , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[44]  P. Scheiffele,et al.  Control of Excitatory and Inhibitory Synapse Formation by Neuroligins , 2005, Science.

[45]  T. Südhof,et al.  Selective Capability of SynCAM and Neuroligin for Functional Synapse Assembly , 2005, The Journal of Neuroscience.

[46]  Ann Marie Craig,et al.  Neurexins Induce Differentiation of GABA and Glutamate Postsynaptic Specializations via Neuroligins , 2004, Cell.

[47]  S. Raghavachari,et al.  Properties of quantal transmission at CA1 synapses. , 2004, Journal of neurophysiology.

[48]  E. Isacoff,et al.  Neurexin mediates the assembly of presynaptic terminals , 2003, Nature Neuroscience.

[49]  T. Südhof,et al.  α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis , 2003, Nature.

[50]  T. Sejnowski,et al.  Independent Sources of Quantal Variability at Single Glutamatergic Synapses , 2003, The Journal of Neuroscience.

[51]  Terrence J Sejnowski,et al.  A Monte Carlo model reveals independent signaling at central glutamatergic synapses. , 2002, Biophysical journal.

[52]  D. Rusakov.  The role of perisynaptic glial sheaths in glutamate spillover and extracellular Ca(2+) depletion. , 2001, Biophysical journal.

[53]  R. Fetter,et al.  Neuroligin Expressed in Nonneuronal Cells Triggers Presynaptic Development in Contacting Axons , 2000, Cell.

[54]  R. Tsien,et al.  Variability of Neurotransmitter Concentration and Nonsaturation of Postsynaptic AMPA Receptors at Synapses in Hippocampal Cultures and Slices , 1999, Neuron.

[55]  D. Kullmann,et al.  Extrasynaptic Glutamate Diffusion in the Hippocampus: Ultrastructural Constraints, Uptake, and Receptor Activation , 1998, The Journal of Neuroscience.

[56]  T. Südhof,et al.  Binding of neuroligins to PSD-95. , 1997, Science.

[57]  T. Südhof,et al.  Distinct Ca2+ and Sr2+ Binding Properties of Synaptotagmins , 1995, The Journal of Biological Chemistry.

[58]  Y. Goda,et al.  Two components of transmitter release at a central synapse. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[59]  D. Kullmann.  Amplitude fluctuations of , 1994, Neuron.

[60]  B. Sakmann,et al.  Quantal components of unitary EPSCs at the mossy fibre synapse on CA3 pyramidal cells of rat hippocampus. , 1993, The Journal of physiology.

[61]  J. Aten,et al.  Measurement of co‐localization of objects in dual‐colour confocal images , 1993, Journal of microscopy.

[62]  T. Südhof,et al.  Distinct Ca and Sr Binding Properties of Synaptotagmins DEFINITION OF CANDIDATE Ca SENSORS FOR THE FAST AND SLOW COMPONENTS OF NEUROTRANSMITTER RELEASE* , 1995 .

[63]  D. Kullmann.  Amplitude fluctuations of dual-component EPSCs in hippocampal pyramidal cells: implications for long-term potentiation. , 1994, Neuron.