Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation

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 retardati...

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Published in:The Journal of neuroscience Vol. 33; no. 23; p. 9699
Main Authors: Raynaud, Fabrice, Janossy, Andrea, Dahl, Janine, Bertaso, Federica, Perroy, Julie, Varrault, Annie, Vidal, Michel, Worley, Paul F, Boeckers, Tobias M, Bockaert, Joël, Marin, Philippe, Fagni, Laurent, Homburger, Vincent
Format: Journal Article
Language:English
Published: United States 05.06.2013
Subjects:
Amino Acid Sequence
Animals
Dendritic Spines - metabolism
Exocytosis - physiology
Female
GTPase-Activating Proteins - genetics
GTPase-Activating Proteins - metabolism
HEK293 Cells
Hippocampus - metabolism
Humans
Long-Term Potentiation - physiology
Male
Mice
Microfilament Proteins
Molecular Sequence Data
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Organ Culture Techniques
Protein Binding - physiology
Random Allocation
Rats
Rats, Sprague-Dawley
Receptors, AMPA - metabolism
Synapses - metabolism
ISSN:1529-2401, 1529-2401
Online Access:Get more information
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Summary: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.
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ISSN:1529-2401
1529-2401
DOI:10.1523/JNEUROSCI.2725-12.2013