title: Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation.
abstract: Synaptic long-term potentiation (LTP) is a key mechanism involved in learning and memory, and its alteration is associated with mental disorders. Shank3 is a major postsynaptic scaffolding protein that orchestrates dendritic spine morphogenesis, and mutations of this protein lead to mental retardation and autism spectrum disorders. In the present study we investigated the role of a new Shank3-associated protein in LTP. We identified the Rho-GAP interacting CIP4 homolog 2 (Rich2) as a new Shank3 partner by proteomic screen. Using single-cell bioluminescence resonance energy transfer microscopy, we found that Rich2-Shank3 interaction is increased in dendritic spines of mouse cultured hippocampal neurons during LTP. We further characterized Rich2 as an endosomal recycling protein that controls AMPA receptor GluA1 subunit exocytosis and spine morphology. Knock-down of Rich2 with siRNA, or disruption of the Rich2-Shank3 complex using an interfering mimetic peptide, inhibited the dendritic spine enlargement and the increase in GluA1 subunit exocytosis typical of LTP. These results identify Rich2-Shank3 as a new postsynaptic protein complex involved in synaptic plasticity.
authors.affiliation: Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR)-5203, Institut de Génomique Fonctionnelle, Montpellier, F-34094, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Raynaud
authors.forename: Andrea
authors.initials: A
authors.lastname: Janossy
authors.forename: Janine
authors.initials: J
authors.lastname: Dahl
authors.forename: Federica
authors.initials: F
authors.lastname: Bertaso
authors.forename: Julie
authors.initials: J
authors.lastname: Perroy
authors.forename: Annie
authors.initials: A
authors.lastname: Varrault
authors.forename: Michel
authors.initials: M
authors.lastname: Vidal
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.forename: Joël
authors.initials: J
authors.lastname: Bockaert
authors.forename: Philippe
authors.initials: P
authors.lastname: Marin
authors.forename: Laurent
authors.initials: L
authors.lastname: Fagni
authors.forename: Vincent
authors.initials: V
authors.lastname: Homburger
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D049229:Dendritic Spines / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D051379:Mice; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009924:Organ Culture Techniques; D011485:Protein Binding / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; C539906:ARHGAP44 protein, human; C492356:Shank3 protein, mouse