Regulation of NMDA-Receptor Synaptic Transmission by Wnt Signaling

Abstract

Wnt ligands are secreted glycoproteins controlling gene expression and cytoskeleton reorganization involved in embryonic development of the nervous system. However, their role in later stages of brain development, particularly in the regulation of established synaptic connections is not known. We found that Wnt-5a acutely and specifically up-regulates synaptic NMDAR currents in rat hippocampal slices facilitating induction of LTP, a cellular model of learning and memory. This effect requires an increase in postsynaptic Ca2+ and activation of non-canonical downstream effectors of the Wnt signaling pathway. In contrast, Wnt-7a, an activator of the canonical Wnt signaling pathway, has no effect on NMDAR mediated synaptic transmission. Moreover, endogenous Wnt ligands are necessary to maintain basal NMDAR synaptic transmission adjusting the threshold for synaptic potentiation. This novel role for Wnt ligands provides a mechanism for Wnt signaling to acutely modulate synaptic plasticity and brain function in later stages of development and in the mature organism.

RoR2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission

“…We found that the time course of activation of PKC is faster than the activation of JNK, suggesting that these kinases could participate in the Wnt5a-induced potentiation of NMDARs via separate mechanisms. Different kinetics of activation induced by Wnt5a also explains why PKC is necessary for a rapid increase in NMDAR-mediated synaptic transmission, whereas JNK seems to potentiate NMDAR currents slowly and in a PKC-independent manner (17). A Wnt ligand considered to be a canonical ligand, Wnt7a, failed to activate PKC and JNK in dendrites but produced a slight increase in the activity of PKC and JNK in the soma of neurons in an RoR2-dependent manner.…”

“…RoR2 signaling activates PKC and JNK, two kinases involved in the rapid up-regulation of NMDAR currents induced by Wnt5a (17). RoR2 signaling is also necessary to maintain basal level of NMDARmediated synaptic transmission.…”

“…Wnt5a, a noncanonical ligand (4), acutely up-regulates the amplitude of NMDAR responses (17), but the mechanism involved in this regulation is not known. We tested whether RoR2 is necessary for this rapid up-regulation of NMDAR currents induced by Wnt5a in hippocampal slices.…”

“…To investigate the signaling mechanism involved in the potentiation of NMDAR currents by activation of RoR2, we tested the hypothesis that RoR2 signals via noncanonical pathways upon activation by noncanonical Wnt ligands. We used genetically encoded biosensors of protein kinase activity to address whether Wnt5a is capable of activating PKC and JNK, two kinases involved in the potentiation of NMDARs currents induced by Wnt5a (17). Kinase activity reporters are based on changes in Förster resonance energy transfer (FRET) as a consequence of kinase-specific phosphorylation; PKC activity reporter (CKAR), when phosphorylated by PKC, decreases FRET (26), whereas JNK activity reporter (JNKAR) increases it (27) (Fig.…”

“…Dysfunction of NMDARs has been implicated in numerous diseases, including Huntington disease, Parkinson disease, depression, bipolar disorder, and schizophrenia (14,15), in which a deficit in NMDAR mediated neurotransmission may be central (16). Interestingly, NMDARmediated currents can be acutely and specifically up-regulated by Wnt5a, a noncanonical Wnt ligand (17), but little is known regarding the signaling pathway and mechanisms involved in such regulation.…”