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Regulatory motifs involved in LRRTM2 trafficking and LRRTM2-dependent stabilisation of AMPARs at excitatory synapses
Synapses are the main site of communication between neurons in the central nervous system. These specialised cell-cell contacts are initiated by cell adhesion molecules at the pre- and post-synapse, which interact with one another to form trans-synaptic complexes, and recruit molecules regulating synapse maturation, specificity and function.
Leucine Rich Repeat Transmembrane Protein 2 (LRRTM2) is a synaptic adhesion molecule that binds to pre-synaptic neurexin and is exclusively localised and enriched at excitatory synapses where it exhibits low membrane dynamics. Interestingly, LRRTM2 is involved in synaptic transmission and plasticity and regulates the surface levels of AMPARs, the main glutamatergic receptors responsible for fast neurotransmission in the brain.
In my PhD, I investigated the molecular mechanisms underlying LRRTM2 stabilisation and trafficking at excitatory synapses, as well as the interplay between LRRTM2 and AMPARs.
We demonstrated that the C-terminal domain of LRRTM2 controls its compartmentalisation in dendrites as well as its enrichment and compaction at synapses. Surprisingly, LRRTM2 synaptic confinement was found to be independent of its PDZ-like binding domain and was instead regulated by a recently identified YxxC intracellular sequence. We further confirmed that this sequence was critical for LRRTM2 trafficking and exocytosis and observed the existence of intracellular LRRTM2-containing vesicles inside spines. Regarding the interplay between LRRTM2 and AMPARs, we showed for the first time, that the recently identified neurexin-binding site in LRRTM2 (E348) is responsible for membrane stabilisation of synaptic AMPARs.
These results demonstrate that the intracellular region of LRRTM2 controls its synaptic clustering, membrane dynamics, and confinement, while extracellular binding interfaces are involved in stabilising AMPARs at the plasma membrane.
Keywords : excitatory synapse, super-resolution microscopy, adhesion molecules, LRRTM2, AMPA receptors
Liouta, K., Chabbert, J., Benquet, S., Tessier, B., Studer, V., Sainlos, M., De Wit, J., Thoumine, O. & Chamma, I. (2021). Role of regulatory C-terminal motifs in synaptic confinement of LRRTM2. Biology of the Cell, 113, 492– 506. https://doi.org/10.1111/boc.202100026
- Présidente : Nathalie Sans, Directrice de recherche, Université de Bordeaux-INSERM
- Rapporteur : Harold Macgilavry, Directeur de recherche, Utrecht University
- Rapportrice : Ana-Luisa Carvalho, Professeur des universités, University of Coimbra
- Examinateur : Gregory Giannone, Directeur de recherche, Université de Bordeaux-CNRS
- Examinatrice : Marianne Renner, Professeure, Sorbonne Université-INSERM
- Directrice de thèse : Ingrid Chamma, Chargée de recherche, Université de Bordeaux