Team : THOUMINE
Interplay between cell adhesion molecules and neuronal activity in synaptic circuit dynamics
Project Leader(s): Mathieu Letellier
The ability of the brain to constantly adapt its organization to ever-changing stimuli is termed ‘plasticity’ and is a prominent feature not only of learning and memory in the adult, but also of neuronal circuit assembly during developmental critical periods. Connections that are the most active become stronger and more stable, while the less active ones weaken and are progressively eliminated. How does activity make a synapse stronger or weaker and how does it serve synaptic circuit refinement? In both immature and mature circuits, long-term changes in synapse function and organization involves signaling which regulate the traffic of synaptic proteins including cell adhesion molecules (CAMs), scaffolding proteins and receptors, but also requires the expression of specific genes through transcription and translation dependent mechanisms.
This research axis aims at understanding the molecular mechanisms by which neurons, together with glial cells, regulate synaptic plasticity at both functional and structural levels in order to (re)organize synaptic circuits while maintaining functional homeostasis.
In the recent years, we demonstrated that individual hippocampal synapses functionally interact with their neighbors through astrocytes and dendritic-dependent signaling (Letellier et al., 2016; 2019) while retaining the capacity to homeostatically regulate their own synaptic strength through mechanisms involving microRNA-dependent local translation (Letellier et al., 2014; Dubes et al., 2019; Dubes et al., 2022). We also investigated the role of CAMs in the control of synaptic differentiation and plasticity and identified a phosphorylation mechanism by which the postsynaptic CAM neuroligin-1 regulates spine formation in parallel of the recruitment and alignment of AMPARs in front of glutamate release sites (Letellier et al., 2018, Haas et al., 2018, Letellier et al., 2020).
Our current work aims at understanding how cell adhesion molecules (CAMs), including neurexin-neuroligin mediated adhesions, regulate the activity-dependent stabilization and remodeling of synaptic circuits and, in turn, how neuronal activity regulates CAMs expression across individual cells and synapses to specify and stabilize synaptic circuits. To reach this objective, we use approaches allowing to label and genetically manipulate activity or CAMs in multiple interconnected neurons and glial cells using single-cell transfection techniques (Letellier et al., 2018; 2019). We investigate the effect of these manipulations on the function, structure and molecular organization of synapses by combining patch-clamp recordings, optogenetics, 3D live imaging and patch-RNA seq techniques in the live brain tissue.
mir124-dependent tagging of glutamatergic synapses by synaptopodin controls non-uniform and input-specific homeostatic synaptic plasticity
Dubes S, Soula A, Benquet S, Tessier B, Poujol C, Favereaux A, Thoumine O, Letellier M. (2022) EMBO J. Jul 25:e109012.
Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation.
Letellier M, Lagardère M, Tessier B, Janovjak H, Thoumine O (2020). eLife 9, pii: e52027.
miRNA-Dependent control of homeostatic plasticity in neurons.
Dubes S, Favereaux A, Thoumine O, Letellier M (2019). Front. Cell. Neurosci. 2019-12-05. 13
Differential role of pre- and postsynaptic neurons in the activity-dependent control of synaptic strengths across dendrites.
Letellier M, Levet F, Thoumine O, Goda Y (2019). PLoS Biol. 17(6): e2006223.
Lattice light sheet microscopy and photostimulation in brain slices.
Ducros M, Getz A, Arizono M, Pecoraro V, Fernandez Monreal M, Letellier M, Nagerl V, Choquet D (2019) Neural Imaging and Sensing. 2019-03-01.
A unique intracellular tyrosine in neuroligin-1 regulates AMPA receptor recruitment during synapse differentiation and potentiation.
Letellier M, Sziber Z, Chamma I, Saphy C, Papasideri I, Tessier B, Sainlos M, Czöndor K, Thoumine O (2018). Nat Commun. 2018-09-28. 9(1).
Pre-post synaptic alignment through neuroligin-1 tunes synaptic transmission efficiency.
Haas KT*, Compans B*, Letellier M*, Bartol TM, Grillo-Bosch D, Sejnowski TJ, Sainlos M, Choquet D, Thoumine O, Hosy E (2018). eLife. 2018-07-25. 7.
Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks.
Letellier M, Park YK, Chater TE, Chipman PH, Gautam SG, Oshima-Takago T, Goda Y (2016). Proc Natl Acad Sci USA. 113(19): E2685-E2694.
Mapping the dynamics and nanoscale organization of synaptic adhesion proteins using monomeric streptavidin.
Chamma I, Letellier M, Butler C, Tessier B, Lim K-H, Gauthereau I, Choquet D, Sibarita J-B, Park S, Sainlos M, Thoumine O (2016). Nat Commun. 7 : 10773.
miR-92a regulates expression of synaptic GluA1-containing AMPA receptors during homeostatic scaling.
Letellier M*, Elramah S*, Mondin M*, Soula A, Penn A, Choquet D, Landry M, Thoumine O, Favereaux A (2014). Nat Neurosci. 17(8) : 1040-1042.
University of Bordeaux, Seed project 2020, ANR AdAdstro 2022