title: Vasodilator-stimulated phosphoprotein (VASP) induces actin assembly in dendritic spines to promote their development and potentiate synaptic strength.
abstract: Dendritic spines are small actin-rich structures that receive the majority of excitatory synaptic input in the brain. The actin-based dynamics of spines are thought to mediate synaptic plasticity, which underlies cognitive processes, such as learning and memory. However, little is known about the molecular mechanisms that regulate actin dynamics in spines and synapses. In this study we show the multifunctional actin-binding protein vasodilator-stimulated phosphoprotein (VASP) regulates the density, size, and morphology of dendritic spines by inducing actin assembly in these structures. Knockdown of endogenous VASP by siRNA led to a significant decrease in the density of spines and synapses, whereas expression of siRNA-resistant VASP rescued this defect. The ability of VASP to modulate spine and synapse formation, maturation, and spine head enlargement is dependent on its actin binding Ena/VASP homology 2 (EVH2) domain and its EVH1 domain, which contributes to VASP localization to actin-rich structures. Moreover, VASP increases the amount of PSD-scaffolding proteins and the number of surface GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) in spines. VASP knockdown results in a reduction in surface AMPAR density, suggesting a role for this protein in regulating synaptic strength. Consistent with this, VASP significantly enhances the retention of GluR1 in spines as determined by fluorescence recovery after photobleaching and increases AMPAR-mediated synaptic transmission. Collectively, our results suggest that actin polymerization and bundling by VASP are critical for spine formation, expansion, and modulating synaptic strength.
authors.affiliation: Department of Biological Sciences and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37235, USA.
authors.forename: Wan-Hsin
authors.initials: WH
authors.lastname: Lin
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Nebhan
authors.forename: Bridget R
authors.initials: BR
authors.lastname: Anderson
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Webb
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism / Q000502:physiology*; D036681:Fluorescence Recovery After Photobleaching; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D015151:Immunoblotting; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000199:Actins; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C092744:ENA-VASP proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D017470:Receptors, Glutamate; C492973:alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptor, human; D000098662:Vasodilator-Stimulated Phosphoprotein; D049452:Green Fluorescent Proteins
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