Wnt-7a Modulates the Synaptic Vesicle Cycle and Synaptic Transmission in Hippocampal Neurons

Abstract

Wnt signaling is essential for neuronal development and the maintenance of the developing nervous system. Recent studies indicated that Wnt signaling modulates long term potentiation in adult hippocampal slices. We report here that different Wnt ligands are present in hippocampal neurons of rat embryo and adult rat, including Wnt-4, -5a, -7a, and -11. Wnt-7a acts as a canonical Wnt ligand in rat hippocampal neurons, stimulates clustering of presynaptic proteins, and induces recycling and exocytosis of synaptic vesicles as studied by FM dyes. Wnt-3a has a moderate effect on recycling of synaptic vesicles, and no effect of Wnt-1 and Wnt-5a was detected. Electrophysiological analysis on adult rat hippocampal slices indicates that Wnt-7a, but not Wnt-5a, increases neurotransmitter release in CA3-CA1 synapses by decreasing paired pulse facilitation and increasing the miniature excitatory post-synaptic currents frequency. These results indicate that the presynaptic function of rat hippocampal neurons is modulated by the canonical Wnt signaling.Wnt signaling regulates crucial processes in all multicellular organisms, including cell proliferation, differentiation, migration, and morphogenesis. Since its discovery about 25 years ago, Wnt signaling has been extensively studied for its diverse roles in embryogenesis and cancer (1) and, more recently, in neural development and synaptic plasticity (2-5). Several studies suggest that Wnt factors play a role in the formation of neuronal connections, and other reports indicate a specific effect on synapse assembly; for example, in Drosophila embryos overexpression of the Wnt gene DWnt-3, encoding a protein localized in axonal processes, disrupted the formation of commissural tracts (6). Wnt-3 also regulates terminal arborization of neurotrophin-3-responsive spinal sensory neurons before the formation of sensory motoneuron synapses (7). In developing cerebellum cortex it has been found that conditioned medium from granule cells increases the diameter of mossy fiber axons and growth cone complexity, a result mimicked by 9). Wingless, the prototypical Drosophila Wnt, and its receptor are localized at the larval neuromuscular junction (10). Wingless is secreted by motoneurons and accumulates at both the pre-and postsynaptic terminals. The loss of Wingless leads to reduction in target-dependent synapse formation (10).The expression of Wnt ligands and proteins of the Wnt signaling machinery in the mature nervous system (11, 12) suggests that Wnt signaling plays a role in neuroprotection and synaptic plasticity in addition to its role in neurite patterning in the developing nervous system (3, 5, 13). Indeed, Wnt ligands can act locally to regulate changes in neuronal cell shape and pre-and postsynaptic terminals, which are thought to underlie changes in synaptic function and learning. Thus, Wnt ligands would appear to be particularly well suited as mediators of synaptic plasticity (5,14,15).In the present study we report that Wnt-7a, a canonical ligand that stimulates vesicle clusteri...

Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca 2+ /Calmodulin-dependent protein kinase II

“…This result suggests that Wnt7a regulates spine number indirectly by increasing the number of presynaptic release sites, which could then stimulate spine formation. Previous studies have reported that Wnt7a does not affect the postsynaptic side (23,40). This apparent discrepancy with our results could be due to the different sources of Wnt7a used (23,40).…”

“…Previous studies have reported that Wnt7a does not affect the postsynaptic side (23,40). This apparent discrepancy with our results could be due to the different sources of Wnt7a used (23,40). Importantly, here we show that postsynaptic activation of Wnt signaling through Dvl1 expression promotes spine growth and excitatory synaptic transmission.…”

“…Wnt7a increases the number of presynaptic release sites through a mechanism that requires Dvl1 and activation of the canonical/Gsk3β Wnt pathway in axons (20,39). Electrophysiological recordings suggest that Wnt7a also regulates glutamate release probability (20,40). Here, we demonstrate that Wnt7a also directly regulates postsynaptic assembly.…”

Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease

“…In fact, we found that Wnt/b-catenin modulates the synaptic vesicle cycle and synaptic transmission in rat hippocampal neurons, 76 and non-canonical Wnt signaling also modulates PSD-95 clustering. 33 Therefore, these possible mechanisms needed to be explored in APP-PS1 animals treated with lithium and rosiglitazone.…”

The Secreted Wnt Antagonist Dickkopf-1 Is Required for Amyloid β-Mediated Synaptic Loss

“…Wnt signals to both sides of the synapse to induce synaptic assembly in the CNS. In axons, Wnts activate a canonical Wnt signaling pathway that requires inhibition of Gsk3 (Ahmad-Annuar et al, 2006;Cerpa et al, 2008b;Davis et al, 2008). On dendrites, Wnts trigger the recruitment of postsynaptic components through the activation of noncanonical pathways (Farías et al, 2009;Cuitino et al, 2010;Ciani et al, 2011).…”