Rapid Activity-Dependent Modifications in Synaptic Structure and Function Require Bidirectional Wnt Signaling

Abstract

Activity-dependent modifications in synapse structure play a key role in synaptic development and plasticity, but the signaling mechanisms involved are poorly understood. We demonstrate that glutamatergic Drosophila neuromuscular junctions undergo rapid changes in synaptic structure and function in response to patterned stimulation. These changes, which depend on transcription and translation, include formation of motile presynaptic filopodia, elaboration of undifferentiated varicosities, and potentiation of spontaneous release frequency. Experiments indicate that a bidirectional Wnt/Wg signaling pathway underlies these changes. Evoked activity induces Wnt1/Wg release from synaptic boutons, which stimulates both a postsynaptic DFz2 nuclear import pathway, as well as a presynaptic pathway involving GSK-3 β/Shaggy. Our findings suggest that bidirectional Wg signaling operates downstream of synaptic activity to induce modifications in synaptic structure and function. We propose that activation of the postsynaptic Wg pathway is required for the assembly of the postsynaptic apparatus, while activation of the presynaptic Wg pathway regulates cytoskeletal dynamics.

Coordinated autoinhibition of F-BAR domain membrane binding and WASp activation by Nervous Wreck

“…This phenotype has not been previously associated with Nwk, but has been observed at early stages of activity-dependent synaptic growth (32,33), as well as in mutants of the cytoskeletal protein Hts/Adducin (34). These structures, known as synaptopods, are thought to mature into "ghost boutons" with active zones but no postsynaptic specialization and to ultimately develop into mature boutons (32,33). In fact, occasional faint accumulations of Dlg could be seen in some Nwk 1-631 -dependent synaptopods (Fig.…”

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

“…Wnt signaling has been implicated in synaptic and morphological plasticity (32,(41)(42)(43)(44). For example, Wnt7a/b protein levels increase in the CA3 region of the hippocampus after environmental enrichment (41).…”

“…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).…”

Synapse development in health and disease

“…Several Wnt pathway components have been implicated in the pathogenesis of schizophrenia and Alzheimer's, raising the question of how this pathway functions at the synapse [33,34]. At the Drosophila NMJ, the Wnt pathway signals bidirectionally to mediate synaptic growth in response to patterned neuronal stimulation [35].…”

“…Single nucleotide polymorphisms in GSK-3β are associated with schizophrenia, and GSK-3β was recently found to interact with DISC1, a major schizophrenia susceptibility gene [33,36]. Postsynaptically, Wnt signaling causes translocation of the cleaved receptor Frizzled into the nucleus, which promotes growth of the postsynaptic membrane [35,37]. Polymorphisms in Wnt signaling components have been linked to neurodegenerative diseases such as Alzheimer's, though whether this lateonset disease is related to Wnt's synaptogenic function is unclear [38].…”