title: Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca²⁺/Calmodulin-dependent protein kinase II.
abstract: The balance between excitatory and inhibitory synapses is crucial for normal brain function. Wnt proteins stimulate synapse formation by increasing synaptic assembly. However, it is unclear whether Wnt signaling differentially regulates the formation of excitatory and inhibitory synapses. Here, we demonstrate that Wnt7a preferentially stimulates excitatory synapse formation and function. In hippocampal neurons, Wnt7a increases the number of excitatory synapses, whereas inhibitory synapses are unaffected. Wnt7a or postsynaptic expression of Dishevelled-1 (Dvl1), a core Wnt signaling component, increases the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs). Wnt7a increases the density and maturity of dendritic spines, whereas Wnt7a-Dvl1-deficient mice exhibit defects in spine morphogenesis and mossy fiber-CA3 synaptic transmission in the hippocampus. Using a postsynaptic reporter for Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) activity, we demonstrate that Wnt7a rapidly activates CaMKII in spines. Importantly, CaMKII inhibition abolishes the effects of Wnt7a on spine growth and excitatory synaptic strength. These data indicate that Wnt7a signaling is critical to regulate spine growth and synaptic strength through the local activation of CaMKII at dendritic spines. Therefore, aberrant Wnt7a signaling may contribute to neurological disorders in which excitatory signaling is disrupted.
authors.affiliation: Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Ciani
authors.forename: Kieran A
authors.initials: KA
authors.lastname: Boyle
authors.forename: Ellen
authors.initials: E
authors.lastname: Dickins
authors.forename: Macarena
authors.initials: M
authors.lastname: Sahores
authors.forename: Derek
authors.initials: D
authors.lastname: Anane
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Lopes
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Gibb
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Salinas
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009024:Morphogenesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; C490507:Wnt7a protein, rat; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2