Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca ²⁺ /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.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...

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Wnt-5a KO results in defects in dopaminergic neurogenesis and neurite development [44,45], and Wnt-7a KO impairs maturation of dopaminergic and other neuronal populations [46][47][48] (Table 1). While Wnt-3a has been described as canonical, Wnt-5a is generally associated with noncanonical Wnt signaling [49], and Wnt-7a is frequently found to play both canonical and noncanonical roles [50 , 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 51].…”

“…Induced proliferation of hESCs/mNSCs [65,66] Recombinant Wnt-3a Induced proliferation and differentiation of hESCs [67] Wnt-4 silencing Impaired early differentiation in hECCs [68] Wnt-5a KO Impaired neurite development in the olfactory bulb (OB) [44] Wnt-1 and Wnt-5a DKO Impaired neurogenesis of midbrain dopaminergic neurons [52] Wnt-5a KO Impaired axon growth and guidance of dopaminergic neurons [45] Wnt-5a CM Increased synaptogenesis and maturation of hippocampal progenitors [69,70] Wnt-5a overexpression Induced axonal differentiation in hippocampal cultures [71] Wnt-7a KO Delayed morphological maturation of glomerular rosettes and synapsin I accumulation [46] Wnt-7a KO Impaired ventral midbrain neurogenesis [47] Wnt-7a and Dvl DKO Defective spine morphogenesis and mossy fiber-CA3 synaptic transmission [48] Wnt-7a Proposed as a key element in the regulation of NSC self-renewal/differentiation; altered spindle- Canonical Wnt receptors are also important for correct neural development (Table 2): FZD3 KO mice show impaired axonal guidance [73] while LRP6 KO mice present cortical defects [74]. Also, FZD1 has been shown to be the receptor for canonical Wnt-1 in mouse tyrosine hydroxylase positive neurons, which activates β-catenin-dependent signaling promoting neuroprotection in dopaminergic neurons [75].…”

“…Wnt-7a 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 similarly increases dendritic spine density and maturity, albeit through a CAMKIIdependent mechanism [48]. On the other hand, knockout of the gene encoding Wnt-7a, results in a decrease in the numbers of newborn neurons in the SGZ and impairs their maturation, linking Wnt-7a both to self-renewal and differentiation [125].…”

The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β-Mediated Synaptic Loss

“…In axons, Wnts activate a canonical Wnt signaling pathway that requires inhibition of Gsk3 (Ahmad-Annuar et al, 2006;Cerpa et al, 2008b;Davis et al, 2008). On dendrites, Wnts trigger the recruitment of postsynaptic components through the activation of noncanonical pathways (Farías et al, 2009;Cuitino et al, 2010;Ciani et al, 2011). Given the role of Wnts in synaptic function, decreased levels of Wnt signaling could contribute to synaptic loss, characteristic of early states of AD.…”

Stem Cells-Based Therapeutics for Parkinson’s Disease - A Transcriptomic Analyses During Dopaminergic Neuron Differentiation under 3- and 2- Dimensional Environments using Human Embryonic Stem Cells

“…The data has shown significant up-regulation of Wnt signaling genes in 3D such as WNT7B, WNT7A and FZD3. WNT7B and WNT7A have been shown to be involved in several developmental processes, including regulation of cell fate and patterning during embryogenesis [13][14][15]. The gene FZD3 has previously been reported that mutant mice with defects in frizzled family receptors such as FZD3 showed a severe impairment of midbrain morphogenesis [13,16].…”