Abstract
SummaryThe structural and functional plasticity of synapses is critical for learning and memory. Long-term potentiation (LTP) induction promotes spine growth and AMPAR accumulation at excitatory synapses, leading to increased synaptic strength. Glutamate initiates these processes, but the contribution from extracellular modulators is not fully established. Wnts are required for spine formation; however, their impact on activity-mediated spine plasticity and AMPAR localization is unknown. We found that LTP induction rapidly increased synaptic Wnt7a/b protein levels. Acute blockade of endogenous Wnts or loss of postsynaptic Frizzled-7 (Fz7) receptors impaired LTP-mediated synaptic strength, spine growth, and AMPAR localization at synapses. Live imaging of SEP-GluA1 and single-particle tracking revealed that Wnt7a rapidly promoted synaptic AMPAR recruitment and trapping. Wnt7a, through Fz7, induced CaMKII-dependent loss of SynGAP from spines and increased extrasynaptic AMPARs by PKA phosphorylation. We identify a critical role for Wnt-Fz7 signaling in LTP-mediated synaptic accumulation of AMPARs and spine plasticity.
Highlights
Induction of long-term potentiation (LTP), the cellular correlate of learning and memory, triggers profound changes in the structure and function of excitatory synapses by increasing dendritic spine size and synaptic strength
It is well documented that entry of Ca2+ through N-methyl-D-aspartate receptors (NMDARs) and activation of Ca2+/calmodulindependent protein kinase II (CaMKII) are key signaling events that lead to spine growth and increased numbers of synaptic a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) (Herring and Nicoll, 2016; Huganir and Nicoll, 2013; Malenka and Bear, 2004)
We examined whether Wnts affect the surface localization of endogenous AMPARs and the innervation of spines containing AMPARs following chemical LTP (cLTP) induction in cultured hippocampal neurons. cLTP increased the percentage of innervated spines, identified by their colocalization with a presynaptic marker, vesicular glutamate transporter 1 (Figures 2A and 2B). cLTP increased the percentage of spines containing AMPAR subunits GluA1 (Figures 2A and 2B) and GluA2 (Figure S2E)
Summary
McLeod et al reveal that Wnt7a-Fz7 signaling is required for LTP-mediated spine plasticity, AMPAR localization, and synaptic strength through the activation of the CaMKII, ERK, and PKA pathways. Their findings demonstrate that extracellular Wnt proteins are crucial upstream initiators of LTP-mediated structural and function synaptic plasticity. Highlights d LTP-mediated spine plasticity and AMPAR trafficking require Wnt-Fz7 signaling d LTP induction rapidly elevates Wnt7a/b protein at spines d Wnt7a induces the fast recruitment of synaptic and extrasynaptic AMPARs d Wnt7a-Fz7 promotes synaptic AMPAR localization via CaMKII, PKA, and ERK cascades.
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