Frizzled-5, a receptor for the synaptic organizer Wnt7a, regulates activity-mediated synaptogenesis

Abstract

SUMMARYWnt proteins play a crucial role in several aspects of neuronal circuit formation. Wnts can signal through different receptors including Frizzled, Ryk and Ror2. In the hippocampus, Wnt7a stimulates the formation of synapses; however, its receptor remains poorly characterized. Here, we demonstrate that Frizzled-5 (Fz5) is expressed during the peak of synaptogenesis in the mouse hippocampus. Fz5 is present in synaptosomes and colocalizes with the pre-and postsynaptic markers vGlut1 and PSD-95. Expression of Fz5 during early stages of synaptogenesis increases the number of presynaptic sites in hippocampal neurons. Conversely, Fz5 knockdown or the soluble Fz5-CRD domain (Fz5CRD), which binds to Wnt7a, block the ability of Wnt7a to stimulate synaptogenesis. Increased neuronal activity induced by K + depolarization or by high-frequency stimulation (HFS), known to induce synapse formation, raises the levels of Fz5 at the cell surface. Importantly, both stimuli increase the localization of Fz5 at synapses, an effect that is blocked by Wnt antagonists or Fz5CRD. Conversely, low-frequency stimulation, which reduces the number of synapses, decreases the levels of surface Fz5 and the percentage of synapses containing the receptor. Interestingly, Fz5CRD abolishes HFS-induced synapse formation. Our results indicate that Fz5 mediates the synaptogenic effect of Wnt7a and that its localization to synapses is regulated by neuronal activity, a process that depends on endogenous Wnts. These findings support a model where neuronal activity and Wnts increase the responsiveness of neurons to Wnt signalling by recruiting Fz5 receptor at synaptic sites.

Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca 2+ /Calmodulin-dependent protein kinase II

“…For example, Wnt7a/b protein levels increase in the CA3 region of the hippocampus after environmental enrichment (41). Neuronal activity also regulates the expression or secretion of Wnts (32,43) and the synaptic localization of the Wnt receptor Fz5 (45). Importantly, synapse formation induced by high-frequency stimulation is mediated by Wnt-Fz5 signaling (45).…”

“…Neuronal activity also regulates the expression or secretion of Wnts (32,43) and the synaptic localization of the Wnt receptor Fz5 (45). Importantly, synapse formation induced by high-frequency stimulation is mediated by Wnt-Fz5 signaling (45). Until now, the molecular mechanisms by which Wnt signaling regulates morphological plasticity have remained poorly characterized.…”

Wnt Signaling in the Vertebrate Central Nervous System: From Axon Guidance to Synaptic Function

“…Different receptors mediate the synaptogenic activity of Wnts in hippocampal neurons (Davis et al 2008;Varela-Nallar et al 2009;Sahores et al 2010). Gain of function of Fz1 or Fz5 induces the clustering of synaptic vesicle proteins and active-zone proteins.…”

“…Studies of Wnts in the nervous system have significantly contributed to our current understanding of the molecular mechanisms that control neuronal circuit assembly. These studies have also shed light into fundamental aspects of cell signaling such as novel mechanisms of protein secretion (Korkut et al 2009) and receptor dynamics (Sahores et al 2010). Here I review the mechanisms by which Wnts modulate axon guidance and synapse formation in the vertebrate central nervous system.…”

UNC-4 antagonizes Wnt signaling to regulate synaptic choice in the C. elegans motor circuit

“…At the mammalian neuromuscular junction, Wnt activates postsynaptic clustering of acetylcholine receptors and can be provided by either the innervating motor neuron (Henriquez et al, 2008) or by nearby non-neuronal tissues (Jing et al, 2009). In these instances, the Wnt signal is transduced by non-canonical pathways that act locally and apparently do not require transcription (Cerpa et al, 2008;Miech et al, 2008;Purro et al, 2008;Sahores et al, 2010;Budnik and Salinas, 2011). Wnt signals may also act as negative cues at neuromuscular synapses.…”