Wnt5a inhibits K+ currents in hippocampal synapses through nitric oxide production

Abstract

Hippocampal synapses play a key role in memory and learning processes by inducing longterm potentiation and depression. The growth of adult synapses is regulated by the Wnt signaling pathway, in addition to other pathways. Wnt may also regulate the activity of the postsynaptic terminal. We have previously found that Wnt-5a induces nitric oxide (NO) production, which modulates NMDA expression in the postsynaptic regions of hippocampal neurons. Because the activity of Kv3.2 channels can be inhibited by NO, we investigated whether Wnt-5a can regulate potassium currents in rat hippocampal neurons.Wnt-5a activates non-canonical Wnt/Ca 2+ signaling; triggering NO production, which in turn inhibits a sustained voltage-dependent K + current. The inhibition of the potassium current is mediated at least in part by ROR2, one of the three previously identified Wnt-5areceptors. Preincubation with the soluble Frizzled receptor protein (sFRP-2), which is a Wnt antagonist, and 7-nitroindazole (7-NI), which is a specific inhibitor of neuronal NO synthase, eliminates the inhibitory effect on the K + current. We conclude that Wnt-5aproduces NO and decreases potassium amplitude currents via NO, demonstrating a novel mechanism by which Wnt-5a may regulate the excitability of hippocampal neurons.

Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients

“…This hypothesis is supported by the decrease in excitability by Li and VPA treatments in LR and NR neurons, respectively, and by the induction of hyperexcitability in control neurons by downregulation of LEF1. The relationship between Wnt signaling, neuronal excitability and synapse formation in the hippocampus has been observed previously [35,[91][92][93][94][95][96]. For example, WNT5A and WNT7A stimulate excitatory synapse formation in hippocampal neurons.…”

Differential Changes in the Number and Morphology of the New Neurons after Chronic Infusion of Wnt7a, Wnt5a, and Dkk‐1 in the Adult Hippocampus In Vivo

“…On the other hand, similar effects to those we have observed after chronic Wnt5a exposure have been reported as a consequence of an experimentally induced status epilepticus, in which a growing number of new neurons with an altered pattern in the location of their processes was found (Parent et al, ). Previous reports showed that Wnt activation through Wnt5 and Wnt3 modulates firing activity in the hippocampus (Oliva and Inestrosa, ), and increases the synaptic transmission and the number of the EPSPs in hippocampal slices (Parodi et al, ). Therefore, it is feasible to speculate that chronically infused Wnt5a might increase the basal hippocampal excitability, and also participates in the development of the abnormal pattern of neurite growth we found.…”

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…CAMKII activates a pathway that inhibits nuclear β-catenin, thereby inactivating Wnt/β-catenin transcriptional activity. The increase in cytosolic Ca 2+ has also recently been linked to production of nitric oxide (NO) in neurons, which influences synaptic excitability through modulation of potassium (K + ) channels [22]. …”

“…To modulate NMDAR synaptic transmission in hippocampal neurons, Wnt5a signals through receptor tyrosine-kinase-like orphan receptor 2 (Ror2) [217], a well-characterized Wnt receptor implicated in both Wnt/Ca 2+ and Wnt/PCP pathways [218,219]. This Wnt5a-Ror2-Ca 2+ -NO pathway also regulates hippocampal excitability by inhibiting voltage-gated K + currents (Kv currents) [22]. Kv channels play key roles in the spiking patterns of hippocampal neurons [220], and are thus important regulators of synaptic plasticity [221].…”