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.Wnt7a | Dvl1 mutant | plasticity T he formation of functional neuronal circuits requires the assembly of different types of synapses with great specificity. The development of an appropriate balance of glutamatergic excitatory and GABAergic inhibitory synapses (E/I ratio) is essential for proper circuit function (1, 2) because an imbalance in the E/I ratio can result in neurological disorders (3-5). Some synaptogenic factors regulate both excitatory and inhibitory synapses (6, 7), whereas other synaptic organizers are more specific (8-10). However, the precise mechanisms by which synaptic organizing signals regulate excitatory and inhibitory synapses remain poorly understood.In the central nervous system, most excitatory inputs are located on dendritic spines, postsynaptic protrusions that function as domains where synaptic activity is regulated in a compartmentalized manner (11-13). Several intracellular molecules have been implicated in the formation and maturation of dendritic spines (14-16), but the mechanisms by which extracellular factors signal through intracellular regulators to promote spine development and maturation remain poorly characterized.Wnt secreted proteins are synaptic organizers that stimulate the formation of central and peripheral synapses (17-19) by promoting presynaptic assembly (20) and the clustering of postsynaptic components (19,(21)(22)(23)(24). In cultured neurons, Wnt5a regulates postsynaptic development of both GABAergic and glutamatergic synapses (24,25). However, it is unclear whether other Wnts play a...

Extensive evidence supports a central role for amyloid-␤ (A␤) in the pathogenesis of Alzheimer's disease (AD). Synaptic loss mediated by A␤ in early stages of the disease might contribute to cognitive impairments. However, little is known about the mechanism by which A␤ induces the loss of synapses. The expression of the Wnt antagonist Dickkopf-1 (Dkk1) is increased in brains of AD patients and in AD transgenic mouse models, suggesting that dysfunction of Wnt signaling could contribute to AD pathology. Here we report that acute exposure to A␤ oligomers induces Dkk1 expression together with the loss of synaptic sites. Importantly, Dkk1-neutralizing antibodies suppress A␤-induced synapse loss in mouse brain slices. In mature rat hippocampal neurons, Dkk1 decreases the number of synapses without affecting cell viability. Ultrastructural analyses revealed that Wnt blockade decreases the size of presynaptic and postsynaptic terminals. Time-lapse recordings of RFP-labeled stable synaptic sites demonstrate that Dkk1 induces the dispersal of synaptic components. These findings identify Dkk1 as a potential therapeutic target for the treatment of AD.

A proper balance between synapse assembly and disassembly is crucial for the formation of functional neuronal circuits and synaptic plasticity in the adult brain. During development, synaptogenesis generates a vast excess of synapses, which are subsequently eliminated. Importantly, aberrant synaptic disassembly during development underpins many neurological disorders. Wnt secreted proteins are robust synaptogenic factors that regulate synapse assembly and function in the developing and mature brain. Recent studies show that Wnt blockade with the antagonist Dickkopf-1 (Dkk1) induces the rapid disassembly of synapses in mature neurons. Importantly, Dkk1 mediates synaptic loss induced by Amyloid-ß, a key pathogenic molecule in Alzheimer’s disease (AD). These findings provide new insights into the potential contribution of dysfunctional Wnt signaling to synaptic loss observed in neurodegenerative diseases. In this review, we discuss the role of Wnt signaling in vertebrate synaptic assembly, function and maintenance, and consider how dysfunction of Wnt signaling could contribute to synaptic disassembly in neurodegenerative diseases such as AD.