Wnt Enhances NMDA Currents via Noncanonical Pathway

Wnts are a large family of secreted proteins that regulate cell polarity and migration throughout development, from gastrulation to synaptogenesis. Wnt binds to Frizzled receptors along with different coreceptors, leading to activation of Disheveled. Depending on which coreceptor is involved and whether Disheveled is localized to the membrane, Wnt signaling either leads to accumulation of cytoplasmic -catenin, which then enters the nucleus and activates transcription of specific genes (the canonical pathway), or it activates Rho GTPases, calcium influx, protein kinase C (PKC), and/or JNK signaling (noncanonical pathways). Expression of Wnts and their downstream effectors persists in adult CNS and is involved in synaptic plasticity. Cerpa et al. report that Wnt-5a regulates NMDA receptor currents in mouse hippocampal slices. Wnt scavengers reduced NMDA currents, whereas exogenous Wnt-5a increased currents, apparently by increasing the proportion of NMDA receptors incorporating the NR2B subunit. The initial increase required calcium influx and PKC, but sustained increase required JNK signaling.