Wnt-Frizzled Signaling Regulates Activity-Mediated Synapse Formation

Abstract

The formation of synapses is a tightly regulated process that requires the coordinated assembly of the presynaptic and postsynaptic sides. Defects in synaptogenesis during development or in the adult can lead to neurodevelopmental disorders, neurological disorders, and neurodegenerative diseases. In order to develop therapeutic approaches for these neurological conditions, we must first understand the molecular mechanisms that regulate synapse formation. The Wnt family of secreted glycoproteins are key regulators of synapse formation in different model systems from invertebrates to mammals. In this review, we will discuss the role of Wnt signaling in the formation of excitatory synapses in the mammalian brain by focusing on Wnt7a and Wnt5a, two Wnt ligands that play an in vivo role in this process. We will also discuss how changes in neuronal activity modulate the expression and/or release of Wnts, resulting in changes in the localization of surface levels of Frizzled, key Wnt receptors, at the synapse. Thus, changes in neuronal activity influence the magnitude of Wnt signaling, which in turn contributes to activity-mediated synapse formation.

Keywords: Wnt; development; frizzled; neuronal activity; synapse formation.

Figure 1

Overview of the Wnt-Fz signaling cascades. (A) In the canonical pathway, the protein degradation complex consisting of Axin, glycogen synthase kinase-3 (GSK-3), and Adenomatous Polyposis Coli (APC) is active when Wnt is absent. GSK-3 phosphorylates β-catenin, resulting in its degradation. Wnt target genes are not transcribed since the DNA transcription factor T-cell factor/lymphoid enhancer factor (TCF/LEF) is bound to corepressor protein Groucho/transducing-like enhancer of split (TLE). In contrast to when Wnt is present, Wnt signals through the Frizzled (Fz) receptor and its co-receptor low-density lipoprotein receptor-related protein (LRP) 5/6 to activate the cytoplasmic protein Dishevelled (Dvl), which functions as a scaffold to regulate local Wnt signaling. Activation of the pathway disrupts the protein degradation complex. β-catenin subsequently translocates into the nucleus and binds to TCF/LEF, increasing the transcription of Wnt target genes. (B) In the planar cell polarity (PCP) pathway, Wnt-Fz signaling through Dvl leads to the activation of RhoA and Rac. The subsequent activation of ROCK and Jun N-terminal kinase (JNK) promotes changes in the cytoskeleton. (C) In the calcium pathway, Wnt-Fz signaling through Dvl activates phospholipase C (PLC), increasing the levels of inositol triphosphate (IP₃) and diacyl glycerol (DAG). This results in an increase in intracellular calcium concentration and activation of the calcium-sensitive effectors protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), triggering changes in gene transcription, cell movement, and actin polymerization.

Figure 2

Regulation of the synaptic localization of AMPARs by Wnt7a-Fz7 signaling. Wnt7a binds to the Frizzled 7 (Fz7) receptor present at dendritic spines and activates PKA, resulting in an increase in extrasynaptic AMPARs through phosphorylation of the GluA1 subunit of AMPARs at serine (S) 845. Wnt7a might also regulate the subsequent movement of extrasynaptic AMPARs to the synapse by lateral diffusion. In addition, Wnt7a-Fz7 signaling activates calcium/calmodulin-dependent protein kinase II (CaMKII), which phosphorylates synaptic Ras GTPase-activating protein (SynGAP) and activates Ras-ERK signaling, resulting in increased levels of AMPARs at dendritic spines.

Figure 3

Cooperativity between neuronal activity and Wnt7a signaling in synapse formation. Under basal conditions, Wnt7a is present at the synapse. A fraction of Frizzled 5 (Fz5) receptor is also localized to both sides of the synapse, with relatively moreof the receptor at the presynaptic side. Changes in neuronal activity such as high-frequency stimulation (HFS) increase the expression and/or release of Wnt7a. In turn, Wnt7a increases the proportion of synaptic surface Fz5, thus changing the magnitude of Wnt signaling and contributing to activity-mediated synapse formation. However, it is unknown if the levels or localization of Fz5 at the postsynaptic side are modulated by neuronal activity.

Figure 4

Wnt ligands promote synapse formation through different Fz receptors. Wnt7a signaling through Frizzled 5 (Fz5) and Fz7 is required for presynaptic assembly and dendritic spine formation respectively. Wnt5a through Fz9 is also sufficient but not required for the formation of dendritic spines.