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  • Introduction Induction of long term potentiation LTP the cel

    2024-02-22

    Introduction 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. Significant progress has been made in understanding the intracellular pathways underlying LTP. It is well documented that entry of Ca2+ through N-methyl-D-aspartate receptors (NMDARs) and activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) are key signaling events that lead to spine growth and increased numbers of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic igf ir receptors (AMPARs) (Herring and Nicoll, 2016, Huganir and Nicoll, 2013, Malenka and Bear, 2004). Both lateral diffusion and exocytosis of AMPARs at the postsynaptic membrane contribute to increased synaptic AMPARs during LTP (Henley and Wilkinson, 2016, Opazo and Choquet, 2011, Penn et al., 2017). Phosphorylation of the AMPAR subunit GluA1 at serine 845 (S845) by protein kinase A (PKA) (Roche et al., 1996) promotes the trafficking of AMPARs to extrasynaptic sites (Esteban et al., 2003, He et al., 2009, Man et al., 2007, Oh et al., 2006, Yang et al., 2008a), which then move to the synapse by lateral diffusion (Borgdorff and Choquet, 2002, Makino and Malinow, 2009). In addition, CaMKII activation leads to membrane insertion and trapping of AMPARs at the synapse during LTP (Esteban et al., 2003, Hayashi et al., 2000, Opazo et al., 2010). Although activation of NMDARs by glutamate initiates these signaling events, the role of other signals in LTP induction is poorly understood. Synaptic modulators that are regulated by neuronal activity can also contribute to LTP-induced intracellular signaling. For example, brain-derived neurotrophic factor (BDNF), which increases during LTP (Castrén et al., 1993, Verpelli et al., 2010), modulates AMPAR incorporation at the synapse (Caldeira et al., 2007) and promotes spine plasticity (Harward et al., 2016, Tanaka et al., 2008, Zagrebelsky and Korte, 2014). Another major class of synaptic organizers are Wnt-secreted proteins, which are regulated by activity and play a critical role in synapse formation and synaptic transmission (Budnik and Salinas, 2011, Ciani et al., 2015, Dickins and Salinas, 2013). Neuronal activity enhances the release of Wnt proteins at the Drosophila neuromuscular junction (NMJ) (Ataman et al., 2008) and increases the expression and/or release of Wnts in hippocampal neurons (Chen et al., 2006, Gogolla et al., 2009, Wayman et al., 2006). Presynaptically, Wnts regulate neurotransmitter release (Cerpa et al., 2008, Ciani et al., 2015). In addition, Wnt proteins postsynaptically increase surface NMDAR levels, promote spine growth, and enhance synaptic strength (Cerpa et al., 2011, Cerpa et al., 2015, Ciani et al., 2011, McQuate et al., 2017). Although a role for Wnts in LTP has been proposed (Cerpa et al., 2011, Chen et al., 2006, Ivanova et al., 2017, Marzo et al., 2016), their precise function in synaptic plasticity and the mechanisms involved remains elusive. Here we examined the contribution of Wnt signaling to LTP-associated spine plasticity and AMPAR trafficking. Acute blockade of endogenous Wnts in the hippocampus prevented LTP-dependent increase in synaptic strength and AMPAR localization. LTP induction at Schaffer collateral (SC)-CA1 synapses rapidly increased endogenous Wnt7a/b levels in this region of the hippocampus and at dendritic spines. Loss- and gain-of-function studies showed that Frizzled-7 (Fz7) receptors are required for Wnt7a-mediated spine plasticity and AMPAR localization during LTP. Fz7-deficient principal neurons in the hippocampus exhibited an impaired synaptic potentiation following pairing-induced LTP. Moreover, live imaging of surface super-ecliptic pHluorin (SEP)-tagged GluA1 construct (SEP-GluA1) and quantum dot-tagged GluA1 revealed that Wnt7a rapidly increased the number of AMPARs and reduced their mobility at synapses. Similar to LTP induction, Wnt7a through Fz7 increased phosphorylation of GluA1 at S845 and induced both loss of synaptic Ras-guanosine triphosphatase (GTPase)-activating protein (SynGAP) from spines in a CaMKII-dependent manner and activation of the Ras-extracellular signal-regulated kinase (ERK) pathway, a process that contributes to spine growth and AMPAR recruitment at synapses (Araki et al., 2015, Patterson et al., 2010). Collectively, our results identify a role for Wnts, acting postsynaptically through the Fz7 receptor, as key extracellular signals stimulating spine plasticity and AMPAR synaptic localization during the initial stages of LTP.