Institut de biologie de l’école normale supérieure

INSERM 1024 - CNRS 8197
Director: Antoine Triller

       

Cellular biology of the synapse | Antoine Triller

  • Goal. To understand the basic mechanisms regulating synaptic function in normal and pathological situations.
  • Background. Neuronal communication takes place at synapses. The action potential in the presynaptic neuron leads to the release of transmitters that dif- fuse in the synaptic cleft and in turn bind to receptors located on the postsynaptic neuron. Receptors are stabilized on the postsynaptic side of the synapse via their interactions with scaffolding proteins. Regu- lation of their number at synapses is a key determinant of synaptic plasticity. Since 2001, by combining methods of cell biology and physics, we have analyzed, at high resolution, the movement of receptors in real time. In 2003, in collaboration with Maxime Dahan, we developed the use for video microscopy of nano-semiconductor particles also known as « quantum dots ». With this approach, the entry and exit of receptors, in and out of synapses, could be seen directly. Furthermore, this single particle tracking (SPT) method has allowed the characterization of the diffusive properties of receptors in submembrane domains and has validated the mechanism of diffusion capture for the stabilization of receptors at central synapses.
  • Recent achievements. By combining single molecule imaging and a morphological approach, we have correlated the physical parameters of receptor diffusion and their organization in the plasma membrane. Using SPT of quantum dots, we have shown that these diffusion properties and receptor scaffold interactions are controlled by the physiological state of the neuron. This provides a mechanism for the regulations of the inhibitory glycine or GABA receptor numbers in the synapse and ultimately for the setting of the inhibitory synaptic strength. We have revealed a new mechanism underlying the early sy- naptic defects in Alzheimer disease. We found that the Aß oligomers bind to a metabotropic glutamate receptor (mGluR5) and that they slow down their lateral diffusion to form aberrant clusters. This elevates intracellular calcium and causes synapse deterioration. An mGluR5 antagonist prevents these deleterious effects. These results reveal a novel mechanism for the early synaptic defects in Alzheimer disease, and provide a promising lead for a pharmacological approach. Meanwhile, Serge Marty has analyzed the three- dimensional organization of the presynaptic active zone of central synapses. For this research he used rapid high-pressure freezing of non-fixed tissue, and thick sections were analyzed by high-resolution electron microscopy tomography. This allowed the visualization of the three-dimensional architecture of the presynaptic terminal cytomatrix. Our aim is to understand, using quasi-instantaneous vitrification, how synaptic vesicles are exocytosed, endocytosed and recycled. Alain Bessis has shown that the activa- tion of microglia induces a delayed impairment of synaptic function. He has further demonstrated that neuronal death is induced by a DAP12- and CD11b-dependent production of reactive oxygen species by microglia. This research has now been extended to establish a link between pathological microglia activation and the regulation of neuronal receptor lateral diffusion and synaptic strength.

Selected Publications

Renner M., Lacor P.N., Velasco P.T., Xu J., Contractor A., Klein W.L., Triller A., Deleterious effects of amyloid ß oligomers acting as an extracellular scaffold for mGluR5. Neuron (2010), 66 — 1-16.

Bannai H., Lévi S., Schweizer C., Inoue T., Launey T., Racine, Sibarita J.B., Mikoshiba K., Triller A., Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics. Neuron (2009), 62 — 670-82.

Lévi S., Schweizer C., Bannai H., Pascual O., Charrier C., Triller A., Homeostatic regulation of GlyR synaptic amount and lateral diffusion. Neuron (2008), 59 — 1-13.

Wakselman S., Béchade C., Roumier A., Bernard D., Triller A., Bessis A., Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. J Neurosci (2008), 28 — 8138-43.

Siksou L., Rostaing P., Lechaire J.P., Boudier T., Ohtsuka T., Fejtová A., Kao H.T., Greengard P., Gundelfinger E.D., Triller A., Marty S., Three-dimensional architecture of presynaptic terminal cytomatrix. J Neurosci (2007), 27 — 6868-77.

Dahan M.,Levi S., Luccardini C., Rostaing P., Riveau B., Triller A., Diffusion dynamics of glycine receptors revealed by single-quantum dot tracking. Science (2003), 302 — 442-5.

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