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Séminaire - Lydia Danglot"Role of vesicular SNAREs in hippocampal pre and post-synaptic assembly"

Abstract :

The central nervous system (CNS) contains billions of neurons, which communicate with each other through highly specialized intercellular junctions: the synapses. During development and plasticity, synaptic molecules are transported to the synapse via vesicular and endosomal carriers. Fusion of these carriers with the synaptic zone, is achieved by SNARE proteins.
We previously studied the role of two vesicular SNARE on presynaptic release of neurotransmitters and showed that Synaptobrevin 2 and TI-VAMP co-exist in hippocampal mossy fibers presynaptic terminals (PNAS 2006). Whereas Synaptobrevin mediates synchronous neurotransmitter release, we showed using the AP-3 mutant mice, that the lack of TI-VAMP in mossy fiber presynaptic terminal was correlated with the loss of an asynchronous release and changes in spontaneous release, indicating that Synaptobrevin and TI-VAMP provide different molecular mechanisms for release at presynaptic sites.

Since, we have recently established knocked out mice for TI-VAMP (Danglot et al., J Neurosci, 2012) which are viable in contrast to Synaptobrevin KO. We are now planning to unravel the specificity of this two neuronal v-SNARE at both pre and post-synaptic sites. Indeed, these two SNAREs are also expressed in post-synaptic compartments which constitute a place of intense trafficking. However, the membrane compartments and the molecular mechanisms involved are still poorly defined. In epithelial cells, we previously showed that TI-VAMP depletion reduces the cell surface amount of tetraspanins known to control EGF receptor localization in microdomains. Depletion of TI-VAMP or tetraspanin CD82 restrains EGFR diffusion at the cell surface as observed by Quantum dots video-microscopy. This is correlated with an increase recruitment of endocytic machinery and impaired MAPK signaling. These results highlight the role of TI-VAMP in receptor traficking, and support a model in which entry of receptors in microdomains could regulate their endocytosis and signaling. Such a mechanism could also operate at the post-synaptic plasma membrane and have a profound impact on the physiology of the synapse. Actually, TI-VAMP Knockout mice display decreased brain weight and increased ventricle volume as measured by MRI. Detailed behavioral characterization unraveled that TI-VAMP knockout was associated with increased anxiety, which suggest a role for TI-VAMP in higher brain functions. We are now unraveling the role of vesicular transport mediated by these 2 SNAREs (synaptobrevin 2 and TI-VAMP), in the dynamics of post-synaptic receptors during synaptogenesis and plasticity using KO mice.

Selected publications

Vezatin is essential for dendritic spine morphogenesis and functional synaptic maturation. Danglot L, Freret T, Le Roux N, Nême NN, Burgo A, Hyenne V, Roumier A, Contremoulins V, Dauphin F, Bizot JC, Vodjdani G, Gaspar P, Boulouard M, Poncer JC, Galli T, Simmler MC. J Neurosci. 2012 Jun 27;32(26):9007-22. doi: 10.1523/JNEUROSCI.3084-11.2012.

Glutamate controls tPA recycling by astrocytes, which in turn influences glutamatergic signals. Cassé F, Bardou I, Danglot L, Briens A, Montagne A, Parcq J, Alahari A, Galli T, Vivien D, Docagne F. J Neurosci. 2012 Apr 11;32(15):5186-99. doi: 10.1523/JNEUROSCI.5296-11.2012.

Absence of TI-VAMP/Vamp7 leads to increased anxiety in mice.Danglot L*, Zylbersztejn K*, Petkovic M*, Gauberti M, Meziane H, Combe R, Champy MF, Birling MC, Pavlovic G, Bizot JC, Trovero F, Della Ragione F, Proux-Gillardeaux V, Sorg T, Vivien D, D'Esposito M, Galli T. *equal contributions. J Neurosci. 2012 Feb 8;32(6):1962-8. doi: 10.1523/JNEUROSCI.4436-11.2012.

Role of TI-VAMP and CD82 in EGFR cell-surface dynamics and signaling.Danglot L, Chaineau M, Dahan M, Gendron MC, Boggetto N, Perez F, Galli T.J Cell Sci. 2010 Mar 1;123(Pt 5):723-35. doi: 10.1242/jcs.062497. Epub 2010 Feb 9.

Loss of AP-3 function affects spontaneous and evoked release at hippocampal mossy fiber synapses. Danglot L*, Scheuber A*, Rudge R*, Raposo G, Binz T, Poncer JC, Galli T. *equal contributions. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16562-7.

Selected reviews
The development of hippocampal interneurons in rodents.Danglot L*, Triller A, Marty S.Hippocampus. 2006;16(12):1032-60. Review. * Corresponding author

Scientific focus :

We aim to understand the mechanisms of formation of neuronal synapses and vesicular trafficking allowing transport of synaptic proteins during maintenance and plasticity of excitatory and inhibitory synapses. To do so, we use classical biochemistry, and molecular and cellular biology technics. We also use multi-scales imaging: at the level of the organism with MRI, at the tissular level with confocal tile imaging. At the cellular and molecular levels we use advanced microscopy technics like spinning disc video-microscopy, single particle tracking with QDOTS and super resolution STORM microscopy.

Christophe Mulle / invitant (mulle @