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DTSTART;TZID=Europe/Paris:20261022T143000
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UID:201275-1792679400-1792679400@www.bordeaux-neurocampus.fr
SUMMARY:Thesis defense - Léa Sarzynski
DESCRIPTION:Venue: Centre Broca \nLanguage of defense:  english \n\nLéa Sarzynski \nIINS \nThesis director: Anna Brachet \nTitle\nDeciphering βII and βIII spectrins organisation and function in the dendritic cytoskeleton \nAbstract\nSpectrins are membrane skeletal proteins ubiquitously expressed in metazoans where they play key roles in regulating cell shape and organisation. As a consequence\, spectrin mutations are associated with a wide range of diseases affecting nearly every organ system\, including cancer\, osteoporosis\, and neurodevelopmental disorders. \nSpectrins typically assemble as α-β tetramers. In mammalian neurons\, αII-spectrin associates with one of three β-spectrins: βII\, βIII\, or βIV. These tetramers bind actin rings to form a periodic lattice repeated every ~190 nm known as the membrane periodic skeleton (MPS)\, a structure unique to neurons and very robust in the axon and its initial segment. \nWhile β-spectrin paralogues are generally segregated into distinct cellular compartments across cell types\, the somatodendritic compartment of neurons presents a notable exception: two paralogues\, βII- and βIII-spectrin\, are co-expressed there. βII-spectrin is conserved across all vertebrates\, whereas βIII-spectrin is evolutionarily more recent and is restricted to mammals. \nMy thesis aimed at investigating the organisation and function of βII and βIII spectrins in dendritic shafts and spines\, both in baseline and during synaptic plasticity. \nUsing advanced super-resolution microscopy techniques\, we showed that the dendritic MPS is built from a dual β-spectrin system in which βII and βIII spectrins are co-expressed and interleaved at the nanoscale within shafts and spine necks. Our results suggest that these paralogues form both homotypic (βII or βIII only) and heterotypic (βII/βIII) tetramers\, with an approximately 100 nm radial periodicity. While either paralogue alone is sufficient to maintain MPS lattice architecture\, their combined loss disrupts MPS integrity altogether. Using targeted mutagenesis\, we further demonstrated that actin binding is required to stabilise both paralogues within the MPS\, whereas βIII-spectrin anchoring additionally depends on phosphoinositide lipids. \nRegarding their role in dendritic spines\, combining imaging and electrophysiology\, we found that although βII- and βIII-spectrin are functionally redundant for MPS integrity\, both are independently required to maintain a correct number of spines and synapses. Detailed characterisation of the remaining spines revealed no effect of spectrin loss on spine morphology or glutamate receptor content (AMPA and NMDA)\, but uncovered a deficit in spine motility\, associated with reduced levels of non-muscle myosin II. \nRegarding synaptic plasticity\, loss of either β-spectrin alone\, or both in combination\, had no effect on long-term depression (LTD)\, but completely abolished long-term potentiation (LTP). To understand this phenotype\, we examined AMPAR molecular behaviour in detail. Using FRAP imaging and super-resolution microscopy\, we found that\, at baseline\, spectrin loss leaves GluA1 quantity unaffected but strongly increases its mobility and disrupts its nanoscale organisation\, revealing a key role for spectrins in constraining AMPAR diffusion and clustering. This disorganisation doesn’t impact basal synaptic transmission but impairs LTP induction and maintenance. \nAltogether\, our findings reveal that\, unlike the axonal MPS\, the dendritic MPS is a composite scaffold in which structural redundancy coexists with paralogue-specific regulatory mechanisms\, mainly identified for lipid binding so far. Despite this redundancy\, both spectrins are individually required for proper spine number and for LTP\, highlighting distinct layers of structural and functional control within a single membrane skeletal system. \nKey words: spectrin ; cytoskeleton ; dendrite \nJury\n\nFlavie Lavoie-Cardinal (CERVO\, Université Laval\, Canada):  Spokesperson\nJosé A. Esteban (CBM Severo Ochoa\, Madrid\, Espagne):  Spokesperson\nMarina Mikhaylova (AG Optogenetics\, Université de Berlin\, Allemagne): Examinator\nChristophe Leterrier (INP\, Université Aix-Marseille): Examinator\nNathalie Sans (Neurocentre Magendie\, Université de Bordeaux): Examinator\n\n  \n  \n
URL:https://www.bordeaux-neurocampus.fr/en/event/thesis-defense-lea-sarzynski/
LOCATION:Amphi Centre Broca Nouvelle Aquitaine\, Université de Bordeaux\, 146 Rue Léo Saignat\, Bordeaux\, France\, France
CATEGORIES:Thesis
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