Wnt signaling modulates pre- and postsynaptic maturation: Therapeutic considerations


  • Ginny G. Farías,

    1. Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología “Joaquín V. Luco” (CRCP), Instituto Milenio (MIFAB), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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  • Juan A. Godoy,

    1. Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología “Joaquín V. Luco” (CRCP), Instituto Milenio (MIFAB), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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  • Waldo Cerpa,

    1. Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología “Joaquín V. Luco” (CRCP), Instituto Milenio (MIFAB), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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  • Lorena Varela-Nallar,

    1. Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología “Joaquín V. Luco” (CRCP), Instituto Milenio (MIFAB), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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  • Nibaldo C. Inestrosa

    Corresponding author
    1. Centro de Envejecimiento y Regeneración (CARE), Centro de Regulación Celular y Patología “Joaquín V. Luco” (CRCP), Instituto Milenio (MIFAB), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
    • CARE & CRCP Biomedical Center, P. Universidad Católica de Chile, Alameda 340, PO-Box 8331010, Santiago, Chile
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Wnt signaling regulates a wealth of aspects of nervous system development and function in embryonic stages and in adulthood. The expression of Wnt ligands and components of the Wnt signaling machinery in early stages of neural development has been related to its role in neurite patterning and in synaptogenesis. Moreover, its expression in the mature nervous system suggests a role for this pathway in synaptic maintenance and function. Therefore, it is of crucial relevance the understanding of the mechanisms by which Wnt signaling regulates these processes. Herein, we discuss how different Wnt ligands, acting through different Wnt signaling pathways, operate in pre- and postsynaptic regions to modulate synapse structure and function. We also elaborate on the idea that Wnt signaling pathways are a target for the treatment of neurodegenerative diseases that affect synaptic integrity, such as Alzheimer's disease. Developmental Dynamics 239:94–101, 2010. © 2009 Wiley-Liss, Inc.


Many lines of evidence have suggested an important role for Wnt signaling pathways in neuronal development and neuronal maintenance (Salinas and Zou,2008). Wnt ligands and other components of the Wnt pathway are found in the nervous system throughout development and in the mature nervous system, where this signaling pathway participates in synaptic function and in the prevention of synaptic failure in Alzheimer's disease (AD) (Table 1).

Table 1. Summary of the Expression and Function of Several Wnt Signaling Pathway Components in Mammalian Central Nervous System (CNS)
Expression in CNSDevelopmental stageWnt components associates function
  • [1–6], [1,5]

    Wayman et al.,2006;

  • [1–6], [2–4]

    Krylova et al.,2002;

  • [1–6], [2–4], [3,5,19], [3,19], [3,10], [3]

    Purro et al.,2008;

  • [1–6], [2–4], [4,5], [4,22,23]

    Hall et al.,2000;

  • [1–6], [1,5], [4,5], [3,5,19], [5], [5,11]

    Rosso et al.,2005;

  • [1–6], [6], [6,14,15]

    Lyuksyutova et al.,2003;

  • [7–9], [7,8,13]

    Shimogori et al.,2004;

  • [7–9], [7,8,13]

    Davis et al.,2008;

  • [7–9], [9,10]

    Cerpa et al.,2008;

  • [9,10], [3,10], [10]

    Farías et al.,2007;

  • [11], [5,11]

    Farías et al.,2009;

  • [12]

    Cerpa et al.,2009;

  • [7,8,13]

    Chacón et al.,2008;

  • [6,14,15]

    Wang et al.,2002;

  • [6,14,15]

    Wang et al.,2006;

  • [16], [16–18]

    Li et al.,2009;

  • [16–18], [17,18]

    Liu et al.,2005;

  • [16–18], [17,18]

    Keeble et al.,2006;

  • [3,5,19], [3,19], [19]

    Ahmad-Annuar et al.,2006;

  • [20,21], [20]

    Yu & Malenka,2003;

  • [20,21], [21]

    Bamji et al.,2003;

  • [4,22,23]

    Lucas et al., 1997;

  • [4,22,23]

    Eickholt et al.,2002.

Wnt2,3a,7a,7b[1–6]Early and late developmentWnt3a,7a induce axon spreading,branching and growth cone[2–4]; Wnt4 induces outgrowth[6]; Wnt2,7b induce dendritogenesis[1,5]; Wnt7a,7b induce synapsin I clustering[4,5]
Wnt3a,4,5a,7a,7b,8b,11[7–9]Mature CNSWnt7a induces presynaptic protein clustering and presynaptic function[9,10]; Wnt5a induces postsynaptic assembly and function[11] and prevents against postsynaptic failure induced by Aβ[12]
Fz 1,2,3,4,5,6,7,8,9,10[7,8,13]Early developmentFz3 mediates growth cone attraction induced by Wnt4[6,14,15]; Fz2 mediates growth cone retraction induced by Wnt5a[16]
Ryk[16–18]Early developmentRyk mediates growth cone retraction[17,18], Ryk mediates axon outgrowth induced by Wnt5a[16]
Dvl[3,5,19]Early and late developmentDvl participates in axon spreading,branching,growth cone[3,19], presynaptic bassoon clustering[19], and dendritogenesis[5]
Mature CNSOverexpression of Dvl induces presynaptic function[19]
β-cat[20,21]Early and late developmentβ-cat participates in dendritogenesis[20] and axonal localization of presynaptic proteins[21]
GSK-3β[4,22,23]Early developmentGSK-3β inactivation induces axon spreading and branching,growth cone[4,22,23]
APC[3,10]Early developmentAPC Regulates the growth cone direction[3].
Mature CNSAPC is requires to presynaptic α7-nAChR clustering[10]
Rac[5]Early DevelopmentRac mediates dendritogenesis induced by overexpression of Dvl[5]
JNK[5,11]Early DevelopmentJNK mediates dendritic branching induced by overexpression of Dvl[5]
Mature CNSJNK mediates postsynaptic PSD-95 clustering induced by Wnt5a[11]

The binding of a Wnt ligand to its receptor could activate different signaling pathways. In the canonical pathway, the binding of the Wnt ligand to its receptor Frizzled (Fz) and co-receptor LRP5/6 leads to the expression of target genes through β-catenin and the TCF/LEF transcription factors (Gordon and Nusse,2006). In addition, two β-catenin–independent pathways have been identified in vertebrates: the Wnt/Ca2+ and the Wnt/planar cell polarity (PCP) pathways (Gordon and Nusse,2006). Interestingly, the same ligand can act through different Wnt pathways depending on the receptor context (Mikels and Nusse,2006). In addition to Fz, there are alternative Wnt receptors such as Ryk and Ror2 (van Amerongen et al.,2008). The interaction of a Wnt ligand with extracellular proteins or other Wnt ligands, as well as the presence of a Wnt gradient, also modulate the signaling activation (Yoshikawa et al.,2003; Tao et al.,2005; Schmitt et al.,2006; Cha et al.,2008; Li et al.,2009) increasing the complexity of the Wnt signaling cascade. Here, we discuss recent discoveries that highlight the importance of Wnt signaling in synaptic assembly and function.


Wnt Function in Axonal Development

The importance of the Wnt pathway has been shown in several model organisms. For example, in Drosophila it has been observed that ectopic expression of Wnt-5 (also known as DWnt-3) disrupted the formation of commissural axon tracts (Fradkin et al.,1995). Mutant embryos for different DWnt signaling components such as Dfrizzled2, Derailed/Ryk, dishevelled, and Armadillo/β-catenin show defects in the precise projection of the axonal growth cone within the nerve cord (Loureiro and Peifer,1998; Yoshikawa et al.,2003; Sato et al.,2006; Bhat et al.,2007). Wnts have been shown to act as attractive or repulsive axon guidance cues, depending on the interaction with different Wnt receptors (Yoshikawa et al.,2003). In Caenorhabditis elegans, multiple Wnts and Wnt receptors, such as Lin-17/Fz and Lin-18/Ryk, regulate axonal growth cones as well as axon outgrowth and branching (Pan et al.,2006; Hilliard and Bargmann,2006; Prasad and Clark,2006). Furthermore, studies in C. elegans motor neurons show that the Wnt pathway mediates axon guidance acting through β-catenin (Maro et al.,2009). In mammals, there is also evidence for a role of Wnt in axon outgrowth and remodeling. Previous studies determined that Wnt-7a increases axonal spreading and branching in cultured granule cells (Lucas and Salinas,1997), and more recently it was determined that Wnt-3a guides and promotes axonal branching and growth cone remodeling in spinal sensory neurons (Krylova et al.,2002, Purro et al.,2008). In granule cells, it has been observed that secreted factors mimic the effect of Wnt-7a causing increased axon and growth cone complexity, and these effects are antagonized by interfering with Wnt signaling (Hall et al.,2000). As well, Wnt-7a mutant mice show a delay in the morphological maturation of glomerular rosettes (Hall et al.,2000).

Mammalian Wnt receptors involved in axon guidance have been intensively studied. Reports indicate that Fz receptors mediate growth cone attraction (Wang et al.,2002,2006; Lyuksyutova et al.,2003), while Ryk receptors mediate growth cone repulsion (Liu et al.,2005; Keeble et al.,2006). Although, a recent report found that Fz receptors could also mediate axon repulsion (Li et al.,2009). It was found that bath application of Wnt-5a increased cortical axon outgrowth through Ryk receptors, and when applied as a gradient, Wnt-5a requires both Ryk and Fz receptors to induce growth cone repulsion (Li et al.,2009). Axons of chick retinal ganglion cell also show graded and biphasic responses to the Wnt-3 ligand in a concentration-dependent manner: high concentrations of Wnt-3 mediate axon repulsion, while low concentrations mediate axon attraction (Schmitt et al.,2006). This evidence suggests that gradients of Wnt ligands act as attractive or repulsive axon cues, probably signaling through different Wnt receptors (Fig. 1A).

Figure 1.

Function of Wnt in the central nervous system (CNS). Scheme summarizing the role of Wnt during CNS development. A,B: During early development, Wnt plays pivotal roles in axon and dendrites. A: In the axon, Wnt participates in processes such as axonal guide, axon attraction or retraction and growth cone (A). B: In dendrites, Wnt plays a role in dendritic branching. C,D: Later on, Wnts act as synaptogenic factors that regulates pre- and postsynaptic differentiation. Presynaptically, Wnt induces the clustering of several presynaptic vesicle proteins, structural presynaptic proteins, and presynaptic receptors (red circles; C); and postsynaptically, Wnt induces the clustering of the postsynaptic scaffold proteins PSD-95 in dendritic spines and glutamate receptors (red circles; D). In mature CNS, Wnt continued expressing and modulating synaptic function.

Some downstream Wnt signaling components have been shown to play a role in axon remodeling. Dishevelled-1 (Dvl1) mutant neurons show defects in microtubule reorganization and axonal remodeling as observed by time-lapse imaging of the neuronal specific-EB3 microtubule plus-ends (Purro et al.,2008). On the other hand, inhibition of glycogen synthase kinase-3β (GSK-3β) mimics Wnt-7a–induced axonal spreading and branching through remodeling of axonal microtubules during postnatal cerebellar development (Lucas and Salinas,1997; Hall et al.,2000). This axonal regulation occurs through GSK-3β–dependent phosphorylation of microtubule associated proteins (MAPs), which in turn influence microtubule dynamics (Goold and Gordon-Weeks,2004). Recently, it was found that inhibition of GSK-3 decreases the level of adenomatous polyposis coli (APC) at microtubule plus-ends of dorsal root ganglion neurons from wild-type or Dvl1 mutant mice. Moreover, APC knockdown induces the formation of enlarged growth cone in wild-type or Dvl1 mutant neurons (Purro et al.,2008). Altogether, this evidence suggests that Wnt participates in axonal remodeling through classic components of the canonical pathway. However, microtubule remodeling induced by Wnt is transcription-independent (Purro et al.,2008), suggesting that a nonconventional canonical Wnt pathway regulates axonal remodeling.

Wnt Function in Dendritic Development

Few reports have evaluated the role of Wnt signaling in dendritic development. In mammals, depolarization induces dendritogenesis, which requires Wnt and β-catenin release (Yu and Malenka,2003). Moreover, it has been observed that neuronal activity enhances the expression of Wnt-2, which stimulates dendritic arborization during development in hippocampal neurons (Wayman et al.,2006). In agreement with these studies, Rosso and collaborators (2005) determined that Wnt-7b increases dendritic branching in hippocampal neurons, an effect that is mimicked by overexpression of Dvl. This effect is mediated by the activation of Rac and JNK signaling in a β-catenin–independent manner (Rosso et al.,2005). This Wnt/Rac/JNK pathway could affect dendritic morphogenesis by modulating the neuronal cytoskeleton.


Wnt Signaling in Presynaptic Assembly

Wnt signaling has also been reported to have a function in presynaptic assembly during development. Studies in the neuromuscular junction (NMJ) of Drosophila have demonstrated a function of Wg, the prototypical Drosophila Wnt, in synaptogenesis, where its loss leads to a reduction in target-dependent synapse formation (Packard et al.,2002). Conversely, in C. elegans, it has been observed that Wnt signaling inhibits synapse formation, suggesting a regulation in the patterning of synaptic connections (Klassen and Shen,2007).

In mammals, Wnt-7a increases the levels of the synaptic vesicle protein synapsin I in developing cerebellar neurons (Lucas and Salinas,1997). Moreover, in Wnt-7a mutant mice, it has been observed a delay in the accumulation of synapsin I (Hall et al.,2000), suggesting a role for this ligand in presynaptic assembly during nervous system development (Fig. 1C). Besides Wnt-7a, Wnt-3a and Wnt-7b also increase the number of excitatory presynaptic puncta in cultured hippocampal neurons (Davis et al.,2008).

Recently, a role for Wnt signaling in presynaptic assembly in the mature central nervous system (CNS) has also been reported. Hippocampal neurons incubated with Wnt-7a show increased numbers of clusters of synaptic vesicle proteins, such as synapsin I, synaptophysin, SV-2, and synaptotagmin (Farías et al.,2007; Cerpa et al.,2008). Of interest, both Wnt-5a and Wnt-7a are highly expressed in the mature CNS, but only Wnt-7a acts presynaptically (Cerpa et al.,2008). A role for Wnt signaling in the clustering of presynaptic receptors also has been studied. Wnt-7a increases the expression of the α7-nicotinic acetylcholine receptor (α7-nAChR), as well as the number and size of α7-nAChR clusters in rat hippocampal neurons (Farías et al.,2007). These studies suggest that specific Wnt ligands can modulate the assembly of the presynaptic terminal in the mature CNS (Fig. 2A).

Figure 2.

Wnt in synaptic function in mature hippocampal neurons. A: Scheme summarizing the Wnt-7a effects on neurotransmitter release. Wnt-7a induces the exocytosis and recycling of vesicles proteins. A possible mechanism involve adenomatous polyposis coli (APC) protein, that in the presence of Wnt-7a ligand, dissociates the β-catenin destruction complex and it associates to the α7-nicotinic acetylcholine receptor (α7-nAChR). It is possible that APC functions as a cargo protein that interacts with microtulules to transport another protein. α7-nAChR localized in the plasma membrane can allow the entry of calcium to modulate the exocytosis of synaptic vesicles and finally to regulate the synaptic transmission. B: Wnt-5a increases synaptic transmission through a postsynaptic mechanism. New PSD-95 clusters are localized in dendritic spines, and they are formed through recruitment from the cytosolic PSD-95 pool. Activation of JNK by Wnt-5a is required for the clustering of PSD-95. Morever, glutamate receptors are anchored to the membrane and can explain the increase in the amplitude of mEPSP.

In the context of these observations, an interesting question arises: which Wnt signaling components are involved in the presynaptic effect? In neurons, Wnt-7a,Wnt-3a, and Wnt-7b activate the canonical Wnt/β-catenin pathway. Moreover, treatment with Dickkopf-1, which promotes internalization of the LRP5/6 co-receptor required for canonical signal activation but not for noncanonical Wnt signaling, resulted in decreased excitatory presynaptic puncta number, indicating that activation of the endogenous canonical pathway contributes to synapse formation (Davis et al.,2008). Following this evidence, it has been proposed that Wnt signaling regulates synapse formation indirectly by promoting neuronal maturation through gene transcription (Waites et al.,2005). However, work of other groups, suggests that the mechanism involved in presynaptic assembly is transcription-independent. In cultured neurons, Wnt signaling increases the number and the size of synaptic vesicle proteins without affecting presynaptic protein expression, before the stabilization of β-catenin and its translocation into the nucleus (Cerpa et al.,2008). In vivo, Wnt deficiency also affects the localization of presynaptic proteins without affecting their levels (Ahmad-Annuar et al.,2006). Similarly, it was observed in conditional mutant mice for β-catenin that this protein is required for the proper localization of synaptic vesicles along the axon, but through a mechanism independent of TCF-mediated transcription (Bamji et al.,2003). In addition, the presynaptic clustering of α7-nAChR induced by Wnt-7a depends on APC but is independent of β-catenin stabilization (Farías et al.,2007). Thus, there appears to be a consensus regarding a transcription-independent mechanism involved in the effect of the Wnt signaling in the presynaptic assembly.

Wnt Signaling in the Postsynaptic Assembly

The functional maturation of the postsynaptic region requires a gradual recruitment of scaffold proteins to anchor receptors to the postsynaptic membrane. Specialized signaling machinery is necessary to cluster receptors and their respective scaffold proteins in the postsynaptic region to form functional synapses (Goda and Davis,2003). Studies on the Drosophila glutamatergic NMJ indicated that loss of Wg results in aberrant development of postsynaptic specializations (Packard et al.,2002). In zebrafish cholinergic NMJ, Wnt-11r organizes the central muscle zone before NMJ formation, affecting the initial prepatterning of AChRs (Jing et al.,2009). Agrin is a classic factor that controls the distribution of the muscle-specific AChR in the mammalian postsynaptic region (Nitkin et al.,1987; Gautam et al.,1996). Diverse components of the various Wnt signaling pathways have been involved in the clustering of this muscle-type receptor. The participation of Dvl and APC in the clustering of the AChR induced by agrin has been demonstrated (Luo et al.,2002; Wang et al.,2003). Recently, it was determined that Wnt-3 induces the rapid formation of unstable AChR micro-clusters during early stages of NMJ assembly in chick wing muscles, which aggregate into large clusters only in the presence of agrin (Henriquez et al.,2008). These results indicate that Wnt-3 acts as a modulator of postsynaptic differentiation at NMJ synapses by collaborating with agrin.

Classic factors that specifically regulate the neuronal postsynaptic region have not been identified. In the peripheral nervous system (PNS), the participation of APC in the localization and anchoring of α3-nAChRs and their scaffold protein PSD-93 at the postsynaptic membrane has been demonstrated (Temburni et al.,2004); however, this study did not elucidate whether Wnt ligands act as synaptogenic factors to modulate postsynaptic assembly.

We have recently found that, in the mature CNS, Wnt-5a but not Wnt-7a increases the number of PSD-95 clusters in dendritic spines (Fig. 1D; Farías et al.,2009). Whether the new clusters of PSD-95 are contained in newly formed protrusions or whether they are formed before, concomitantly, or after the protrusion formation, is being intensively studied. Regarding this issue, an interesting question is how PSD-95 clusters are formed. Four possibilities have been considered: increased expression of PSD-95 protein, decreased levels of PSD-95 per cluster, splitting of pre-existent PSD-95 clusters, and recruitment of PSD-95 from a diffuse pool. Wnt-5a does not decrease the mean intensity or size of PSD-95 clusters, eliminating the possibility of the splitting of pre-existent PSD-95 clusters into new clusters, as previously described (Gerrow et al.,2006). Short-term exposure to Wnt-5a (2 hr), does not increase total PSD-95 levels, indicating that Wnt-5a induces the number of PSD-95 clusters through redistribution of an existing PSD-95 pool. It has been reported that new clusters of PSD-95 can be formed through recruitment of PSD-95 from a cytosolic PSD-95 pool (Bresler et al.,2001). This is the most feasible alternative, considering that Wnt-5a treatment reduces the dendritic diffuse pool of PSD-95 while increasing the membrane attached pool (Farías et al.,2009). In addition to its effect on PSD-95 clustering, Wnt-5a increases the insertion of glutamate receptors in the cell surface (Inestrosa et al.,2007; Cerpa et al.,2009).

How does the Wnt signaling pathway regulate postsynaptic assembly in the mature CNS? Reports indicate that, in the excitatory postsynaptic region, phosphorylation of PSD-95 on Ser-295 by JNK-1 (p46 isoform), modulates the anchoring of PSD-95 to the postsynaptic membrane and the synaptic accumulation of PSD-95 (Kim et al.,2007). Considering this evidence, we wanted to evaluate the participation of Wnt/JNK signaling pathway in the clustering of PSD-95. Studies in mature cultured hippocampal neurons exposed to a specific JNK inhibitor showed that the clustering of PSD-95 induced by Wnt-5a is inhibited by the modulation of JNK activity (Farías et al.,2009). These findings suggest that Wnt-5a modulates the assembly of the excitatory postsynaptic region in mature CNS through activation of the Wnt/JNK signaling pathway (Fig. 2B).


Presynaptic Function

Wnts are also involved in the regulation of synaptic plasticity. Wnt-7a increases the initial rate of synaptic vesicle exocytosis evoked by depolarization in presynaptic terminals of mature hippocampal neurons, suggesting a modulatory effect for this ligand in transmitter release at the presynaptic terminal (Cerpa et al.,2008). In addition, Wnt-7a induces the endocytosis of synaptic vesicles in a very fast and clear way (Cerpa et al.,2008). These results indicate a direct role for Wnt-7a in the synaptic vesicle cycle. Besides, Wnt-3a is released in an activity-dependent manner from glutamatergic synapse (Chen et al.,2006).

Wnt signaling also has a role in synaptic transmission. Electrophysiological recordings at mossy fiber-granule cell synapses indicate that Wnt signaling regulates synaptic function in cerebellar neurons: double mutants for Wnt-7a/Dvl show a significant decrease in the frequency but not in the amplitude of miniature excitatory postsynaptic currents (mEPSCs; Ahmad-Annuar et al.,2006). In adult rat hippocampal slices, Wnt-7a modulates synaptic transmission, where electrophysiological analysis shows an increase in the frequency of mEPSCs and a decrease in the paired pulse facilitation (Cerpa et al.,2008). This indicates that Wnt-7a increases synaptic transmission by a presynaptic mechanism, probably involving an increase in neurotransmitter release.

The mechanism by which Wnt signaling regulates neurotransmitter release remains unknown; however, some data suggest that interaction of Dvl with synaptic vesicle proteins and/or the redistribution of α7-nAChR to the presynaptic terminal (Fig. 2A) are possible mechanisms (Kishida et al.,2007; Salinas and Zou,2008). This suggests a physiological role for the Wnt signaling in functional synaptic transmission in the CNS.

Postsynaptic Function

In the C. elegans NMJ, it has been shown that cam-1/Ror, a Wnt-5a receptor ortholog in Xenopus and mammals (Oishi et al.,2003), is required for the postsynaptic receptor acr-16/α7-nAChR–mediated synaptic transmission in muscle (Francis et al.,2005). In the mammalian CNS, we evaluated the functional consequences of Wnt-5a-induced clustering of PSD-95 in dendritic spines (Farías et al.,2009) and glutamate receptor insertion (Cerpa et al.,2009), in mature hippocampal neurons. Electrophysiological recordings at CA3-CA1 synapses using brain slices revealed that Wnt-5a increases the amplitude of field excitatory postsynaptic potential (EPSP) for both AMPA and NMDA components of the EPSC, without modifying the paired pulse facilitation at a short-term exposure (Cerpa et al.,2009), indicating that the potentiation induced by Wnt-5a is due to postsynaptic modulation of glutamatergic postsynaptic currents. These results suggest that Wnt-5a plays a functional role in the postsynaptic region, probably as a consequence of the increase in PSD-95 clustering (Fig. 2B; Farías et al.,2009). The question of which of the Wnt signaling components modulates the function of the postsynaptic region is under intense study.


Wg affects the pre- and postsynaptic region in Drosophila NMJ (Packard et al.,2002). Recent evidence has emerged regarding how one synaptogenic factor can regulate two distinct synaptic machineries. Ataman et al. (2008) found that Wg acts through different pathways to regulate pre- and postsynaptic boutons at the glutamatergic Drosophila NMJ (Ataman et al.,2008; Miech et al.,2008). In rat cultured hippocampal neurons, Wnt-7a activates the canonical Wnt/β-catenin pathway inducing phosphorylation of Dvl, stabilization and accumulation of β-catenin to induce Wnt target gene expression (Cerpa et al.,2008). The ligand Wnt-5a, however, is unable to induce the stabilization of β-catenin, while it can induce phosphorylation of Dvl, JNK, and CAMKII, which are related to the noncanonical Wnt/JNK and Wnt/Ca2+ pathways respectively (Farías et al.,2009). This evidence suggests that, in the mature nervous system, different Wnt ligands can specifically activate different Wnt pathways. Could this be a differential role for canonical and noncanonical Wnt pathways in the mature nervous system? Our studies, in the mammalian CNS, suggest a compartmentalization of Wnt signaling pathways to regulate synaptic assembly and function. In fact, Wnt ligands that affect presynaptic assembly and function, are ligands that act specifically through the canonical Wnt pathway (Cerpa et al.,2008). Wnt-5a, a ligand that activates noncanonical Wnt components induces the clustering of PSD-95 at the postsynaptic region through the Wnt-5a/JNK pathway, suggesting that different types of ligands define pre- and postsynaptic sites in the mammalian CNS (Fig. 2).


The current AD hypothesis suggests that the neurotoxic Aβ peptide specifically affects central synapses, in the form of Aβ oligomers (Selkoe,2002; Cleary et al.,2005; Lacor et al.,2007). It has been observed that Aβ oligomers associate with regions enriched in PSD-95 (Lacor et al.,2004) and reduce PSD-95 content in both hippocampal neurons in vitro (Roselli et al.,2005) and APP transgenic animals (Almeida et al.,2005). Moreover, electrophysiological analysis in field and intracellular recordings shows that Aβ oligomers reduce very quickly the fEPSP amplitude (20 min) without affecting the paired pulse facilitation. This indicates that the probability of neurotransmitter release does not change in the presence of Aβ and that synaptic depression could be attributed to a postsynaptic mechanism (Cerpa et al.,2009).

Because the Wnt pathway has been involved in the regulation of postsynaptic structuring and function, a relevant question is how Wnt signaling overcomes the synaptotoxic effect of Aβ oligomers (Inestrosa and Toledo,2008; Toledo et al.,2008). Recently, we evaluated the effect of the Wnt-5a ligand on synaptic failure induced by Aβ: Wnt-5a prevents the drastic decrease in the number of PSD-95 clusters triggered by Aβ oligomers in the postsynaptic region after 1 hr of exposure. Of interest, the number of clusters of the presynaptic protein synapsin I was not affected by Aβ (Cerpa et al.,2009), suggesting a specific postsynaptic effect of Aβ at short-term exposure. Aβ oligomers have been shown to affect the interaction between pre- and postsynaptic boutons (Roselli et al.,2005), causing a loss of contacts between the postsynaptic and the presynaptic counterpart, which is prevented by Wnt-5a (Cerpa et al.,2009). In addition, it was determined by electrophysiological analysis that Wnt-5a protects synaptic transmission depressed by Aβ oligomers. Moreover, when Wnt-5a is removed from the perfusion media, a decrease of the EPSCs amplitude induced by Aβ oligomers can be observed (Cerpa et al.,2009). Altogether, these results indicate that Wnt-5a has a protective role against synaptic failure evoked by Aβ oligomers.

The mechanism involved in Wnt-5a–mediated protection of the postsynaptic apparatus has been subjected to further studies; nonetheless, it seems that the Wnt/JNK signaling blocks a critical step in the Aβ-mediated postsynaptic disassembly or in the Aβ-induced degradation of postsynaptic proteins. These findings revealed a potential therapeutic value for the Wnt signaling activation in the treatment of neurodegenerative diseases that affect synaptic integrity, such as AD.


During the formation of synapses, specific regions of pre- and postsynaptic neurons associate to form a single functional transmission unit. In this process, alterations in the structuring of the presynaptic terminal or the postsynaptic region are accompanied by a parallel change in the opposite synaptic side. Herein, we have reviewed the roles of the Wnt signaling pathway from the early axonal and dendritic development until its later participation in synaptic function in the mature nervous system. The expression of Wnt ligands during neurite development and in the mature synapse in the CNS supports the function of Wnts in all these processes. Early in neuronal development, Wnt acts as a pathfinder for axons and dendrites, determining when an axon must elongate, retract, or remodel its cone (Fig. 1A), and when dendrites must branch (Fig. 1B) to finally initiate their interactions. These effects on axonal and dendritic development are early events that should precede synapse formation and maturation. Later on, Wnts may act as synaptogenic factors recruiting several structural and functional proteins to the pre- and postsynaptic region (Fig. 1C,D). Finally, in the mature CNS, Wnts modulate synaptic transmission. Evidence led us to suggest that different Wnt ligands and Wnt signaling pathways are compartmentalized to act specifically in pre- and postsynaptic compartments (Fig. 2). It is possible that Wnt ligands affecting the pre- and postsynaptic regions are secreted by their synaptic counterpart. Future works will aim to elucidate the mechanisms of both Wnt expression and release, as well as putative targets for treatment of neurodegenerative diseases that affect synapse integrity.


G.C.F. and W.C. received a predoctoral fellowship from FONDECYT, and L.V.-N. received a postdoctoral grant from FONDECYT.