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.
Highlights
In the central nervous system, synapses permit the rapid transmission of information from one neuron to another in a unidirectional manner
Fz5 loss-of-function blocks the synaptogenic activity of Wnt7a (Sahores et al, 2010). These results show that Fz5 is a receptor for Wnt7a and that endogenous Wnt7a-Fz5 signaling is required for the assembly of presynaptic boutons in hippocampal neurons
We discussed the role of Wnt signaling in the formation of excitatory synapses during development and in response to neuronal activity
Summary
In the central nervous system, synapses permit the rapid transmission of information from one neuron to another in a unidirectional manner. Dkk-1 reduces the number of synaptic vesicle clusters, suggesting that endogenous Wnts present in hippocampal neuronal cultures activate the canonical pathway to promote presynaptic assembly (Dickins, 2012). The potent and specific Wnt antagonist Dkk-1 abolishes the Wnt7amediated increase in dendritic spine density in cultured hippocampal neurons, indicating that the effect of Wnt7a on dendritic spine formation is regulated by canonical signaling (Ramos-Fernández et al, 2019).
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