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Aberrant Wnt signaling is implicated in various neurological disorders.We are interested in the physiological function and regulation of Wnt signaling in the mammalian brain.Our previous work revealed a critical role of Wnt signaling in synaptic plasticity-a cellular process essential for information storage in the brain.Inhibition of Wnt signaling impaired LTP.Conversely,activation of Wnt signaling potentiated LTP.We also demonstrated that tetanus-mediated LTP induction caused rapid Wnt3Arelease and activation of Wnt signaling in hippocampal slices.Recently,we performed studies to determine how synaptic activity elicits Wnt3A secretion from cultured hippocampal neurons.We observed that Wnt3A was concentrated at synapses.Glutamate stimulation led to depletion of intracellular Wnt3A,which was accompanied by surface expression of Wnt3A and increase of Wnt3A in culture media.The stimulation-induced Wnt3A secretion required NMDA receptor activation,and the NMDA receptor-dependent Wnt3A secretion was blocked by tetanus toxin,suggesting Wnt3A was secreted via a vesicular pathway.We also identified a role of synaptotagmin Ⅳ,a calcium sensor protein,in regulation of Wnt3A secretion.