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Synaptic microstructure, dynamics and molecular interactions

Head of project : Antoine Triller

Three directions are considered here, and through their combination we aim at a deeper understanding of the molecular dynamics at synapses.

1- The transmission of signals between neurons is a function of the molecular organisation of synapses. In other words, the function of a synapse is determined by the number, activity and precise location of its components. In order to explore the ultrastructure of excitatory and inhibitory synapses we use advanced electron microscopy techniques such as high pressure freezing (HPF) and correlative light and electron microscopy (CLEM). In addition, we have implemented photo-activated localisation microscopy (PALM) to elucidate the absolute numbers and distribution of synaptic proteins at super-resolution scale.

Participants : A. Triller, P. Rostaing, F. Niwa, A. Ludwig, P. Serna Martinez, O. Gemin

2- Functional changes at synapses are necessarily the result of dynamic rearrangements of the synaptic structure. Over the last decade our laboratory has investigated the diffusion properties of inhibitory neurotransmitter receptors using single particle tracking (SPT) of quantum dot (QD) tagged receptor subunits at high spatial and temporal resolution. These studies have revealed the dynamic exchange of receptors between the synaptic and the extra-synaptic membrane as well as their immobilisation at synapses. More recently, we have begun to investigate the molecular interactions between receptors and scaffold proteins at synapses using high-density PALM-based single molecule imaging.

Participants : C. Specht, A. Triller, X. Yang, A. Jan, S. Colasse, P. Rostaing

3- Dynamic rearrangements of the synaptic structure are the basis of synaptic plasticity. Using pharmacological and physiological approaches as well as recombinant probes, we explore the upstream signalling processes that regulate the structure and function of synapses in cultured neurons. This includes changes in synaptic activity, activation of signalling molecules and post-translational modifications, the role of the extracellular matrix (ECM) and the presence of diffusion barriers for the dynamic exchange of synaptic components.

Participants : A. Dumoulin, A. Triller, V. Lepetz, P. Rostaing, S. Colasse

Patrizio A, Renner M, Pizzarelli R, Triller A, Specht CG (2017) Alpha subunit-dependent GlyR clustering and regulation of synaptic occupancy. Scientific Reports In press

Renner M, Wang L, Levi S, Hennekinne L, Triller A (2017) A simple and powerful analysis of lateral subdiffusion using single particle tracking. Biophys J in press

Shrivastava AN, Aperia A, Melki R, Triller A (2017) Physico-Pathologic Mechanisms involved in Neurodegeneration : Misfolded Proteins-Plasma Membrane Interactions. Neuron 95(1):33-50 ; doi : 10.1016

Bannai H, Niwa F, Sherwood MW, Shrivastava AN, Arizono M, Miyamoto A, Sugiura K, Lévi S, Triller A, Mikoshiba K (2015) Bidirectional Control of Synaptic GABAAR Clustering by Glutamate and Calcium. Cell Report 13:2768-80

Shrivastava AN, Redeker V, Fritz N, Pieri L, Almeida LG, Spolidoro M, Liebmann T, Bousset L, Renner M, Léna C, Aperia A, Melki R, Triller A (2015) α-synuclein assemblies sequester neuronal 3-Na+/K+-ATPase and impair Na+ gradient. EMBO J 34:2408-23

Specht CG, Izeddin I, Rodriguez PC, El Beheiry M, Rostaing P, Darzacq X, Dahan M, Triller A (2013) Quantitative nanoscopy of inhibitory synapses : counting gephyrin molecules and receptor binding sites. Neuron 79 : 308-321