Hippocampal synapses play a key role in memory and learning processes by inducing long-term potentiation and depression. Wnt signaling is essential in the development and maintenance of synapses via several mechanisms. We have previously found that Wnt5a induces the production of nitric oxide (NO), which modulates NMDA receptor expression in the postsynaptic regions of hippocampal neurons. Here, we report that Wnt5a selectively inhibits a voltage-gated K(+) current (Kv current) and increases synaptic activity in hippocampal slices. Further supporting a specific role for Wnt5a, the soluble Frizzled receptor protein (sFRP-2; a functional Wnt antagonist) fully inhibits the effects of Wnt5a. We additionally show that these responses to Wnt5a are mediated by activation of a ROR2 receptor and increased NO production because they are suppressed by the shRNA-mediated knockdown of ROR2 and by 7-nitroindazole, a specific inhibitor of neuronal NOS. Together, our results show that Wnt5a increases NO production by acting on ROR2 receptors, which in turn inhibit Kv currents. These results reveal a novel mechanism by which Wnt5a may regulate the excitability of hippocampal neurons.

This work was supported by grants from Fondecyt no. 1120156 and from the Basal Centre for Excellence in Science and Technology (Conicyt-PFB 12/2007) to N.C.I; Fondecyt no. 11121206 to WC; the Plan Estatal de I + D + i 2013–2016 and ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (Grant PI13/00408) and FEDER to F.J.M.; grants from the Fundación Ciencia y Vida (CONICYT PFB16/ 2007) and FONDECYT no. 1131137 to I.E.A. and M.V-G.