Evidence for an enhancement of excitatory transmission in adult CNS by Wnt signaling pathway modulation

Canonical Wnt3a Modulates Intracellular Calcium and Enhances Excitatory Neurotransmission in Hippocampal Neurons

“…Wnt3a belongs to the so-called Wnt/␤-catenin or canonical signaling as opposed to the ␤-catenin-independent or noncanonical pathways, which transduce their signals to control asymmetric cell division and morphogenetic movements during vertebrate gastrulation, including the Wnt/Ca 2ϩ pathway (19,20,32). Here we demonstrate that synaptic transmission activity was modulated by direct application of a canonical Wnt3a protein to mature hippocampal neurons, which is in general agreement with the effect of a recombinant Wnt3a preparation used to study long term potentiation events on hippocampal slices (18) and the use of either conditioned medium containing Wnt ligands (15,17) or Wnt/␤-catenin small molecule modulators (16). Moreover, the effect was dependent on the incubation with the purified protein (Figs.…”

“…Finally, the experimental data reported in this study do not necessarily imply that the Wnt3a effect on neurotransmission would be independent of the activity mediated by ␤-catenin T cell factor/lymphoid enhancer factor complexes, which have been previously involved in long term potentiation events (16,18), but rather suggest that such a rapid effect on the neuronal network (i.e. min) involves the cross-talk between receptors and kinases acting as canonical or Wnt/Ca 2ϩ components, which is the molecular machinery associated with or immediately downstream of its complex receptor at the membrane in the Wnt3a effect on synaptic transmission in mature hippocampal neurons.…”

“…In these brain domains Wnt signaling has essential roles in diverse biological processes including neurogenesis (6), axonal remodeling (7), synapse formation, and maintenance of pre-and postsynaptic terminals (8 -14). Indeed, several studies have begun to show that Wnt signaling may also be involved in excitatory synaptic transmission (15)(16)(17)(18). For instance, activation of N-methyl-D-aspartate (NMDA) 3 receptors, after tetanic stimulation in rodent hippocampal slices, induces the release of a pool of vesicles containing Wnt3a in the synaptic terminal modulating long term potentiation events (18).…”

“…Similarly, double-mutant mice for Wnt7a and Dishevelled-1, which exhibit decreases in the number of synapses between mossy fibers of the cerebellum and grainy cells, showed marked deterioration in the release of neurotransmitters and in the recycling of vesicles in the existing synapses (15). Furthermore, pharmacological analysis with drugs modulating Wnt signaling in hippocampal neurons showed an acute increase of neurotransmitters released from the presynaptic component, resulting in enhanced evoked basal activity and frequency of spontaneous and miniature excitatory currents (16). Finally, it has been reported that conditioned media containing canonical Wnt7a and to a lesser extent Wnt3a, but not conditioned media containing the noncanonical Wnt5a, which signals mainly through the Wnt/calcium (Wnt/Ca 2ϩ ) pathway (19,20), were found to increase synaptic transmission in CA3-CA1 slices in adult rat hippocampus and to induce the recycling and exocytosis of synaptic vesicles in hippocampal neurons in culture (17).…”

Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats

“…There is evidence that WNT signaling might be implicated in synaptic plasticity of mature dentate granule cells (Chen et al 2006; see also Beaumont et al 2007). Thus, one should consider the possibility that the lentivirus-based expression of a dnWNT interfered with synaptic plasticity in post-mitotic granule cells.…”