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Role of vSNAREs in post-synaptic AMPAR trafficking, glutamatergic transmission and plasticity
May Bakr
Team Perrais
IINS
Thesis defended in english
Thesis supervisor: David Perrais
Abstract
Synaptic plasticity, the activity-dependent modifications in synaptic strength, is a remarkable feature of the nervous system and has long been postulated as the cellular basis of learning and memory. A well characterized form of synaptic plasticity is long-term potentiation (LTP) of excitatory synaptic transmission in CA1 hippocampal pyramidal neurons. LTP requires the fast recruitment and stabilization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) at postsynaptic sites via the regulated trafficking and exocytosis of recycling endosomes (REs). Exocytosis is mediated by a family of proteins called soluble NSF (N-ethylmaleimide-sensitive fusion protein) attachment protein receptors or SNAREs. These proteins mediate membrane fusion by forming a complex composed of one R-SNARE, usually on one membrane, and two or three Q-SNAREs, usually on the other membrane. The formation of the SNARE complex provides specificity for a controllable fusion as first proposed by Rothman et al in 1993. SNARE proteins have been well characterized for their function in presynaptic vesicle fusion during neurotransmitter release. However, their role in activity-dependent post-synaptic membrane trafficking, and particularly AMPAR trafficking, remained elusive until recently. Given the importance of somato-dendritic recycling in neuronal physiology, our goal was to identify major players of dendritic RE exocytosis. In this study, we identify VAMP4 as the key vesicular SNARE protein that mediates the majority of RE exocytosis in dendrites. In contrast, VAMP2 plays only a minor role even though it was previously identified as critical for the post-synaptic expression of LTP. The knockdown (KD) of VAMP4 reduces the exocytosis frequency of transferrin receptor (TfR), a marker of REs and a surrogate marker of AMPAR trafficking pathways. Surprisingly, expression of tetanus neurotoxin (TeNT), which cleaves VAMP2, does not affect TfR exocytosis. Moreover, VAMP4 KD enhances the fraction of AMPARs at the cell surface and its recycling. Consistent with this result, in organotypic hippocampal slices, VAMP4 KD increases the amplitude of AMPAR mediated excitatory post-synaptic currents (EPSCs) without affecting NMDAR mediated EPSCs in CA1 pyramidal neurons. Finally, VAMP4 KD reduces LTP while TeNT totally blocks it. Our data suggests a model where the depletion of VAMP4 leads to a basal state missorting of AMPARs to the plasma membrane, which consequently impairs LTP possibly via an occlusion mechanism. Additionally, the opposing changes in the levels of both TfR and AMPAR on cell surface upon VAMP4 KD suggest that these receptors may be sorted and trafficked independently. We therefore propose that VAMP4 and VAMP2 mediate functionally distinct and complementary trafficking pathways modulating synaptic strength and plasticity.
Keywords: synapse, synaptic plasticity, AMPA receptor, exocytosis, SNARE, recycling endosome.
Publication
Memory enhancement by ferulic acid ester across species
Science Advances 24 Oct 2018:
Vol. 4, no. 10, eaat6994
DOI: 10.1126/sciadv.aat6994
Jury
Dr. Stéphane OLIET
Dr. Gunnar GOURAS
Dr. Sabine LEVI
Dr. Marie-Claude POTIER