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...

During the formation of synapses, specific regions of pre-and postsynaptic cells associate to form a single functional transmission unit. In this process, synaptogenic factors are necessary to modulate pre-and postsynaptic differentiation. In mammals, different Wnt ligands operate through canonical and noncanonical Wnt pathways, and their precise functions to coordinate synapse structure and function in the mature central nervous system are still largely unknown. Here, we studied the effect of different Wnt ligands on postsynaptic organization. We found that Wnt-5a induces short term changes in the clustering of PSD-95, without affecting its total levels. Wnt-5a promotes the recruitment of PSD-95 from a diffuse dendritic cytoplasmic pool to form new PSD-95 clusters in dendritic spines. Moreover, Wnt-5a acting as a non-canonical ligand regulates PSD-95 distribution through a JNK-dependent signaling pathway, as demonstrated by using the TAT-TI-JIP peptide in mature hippocampal neurons. Finally, using adult rat hippocampal slices, we found that Wnt-5a modulates glutamatergic synaptic transmission through a postsynaptic mechanism. Our studies indicate that the Wnt-5a/JNK pathway modulates the postsynaptic region of mammalian synapse directing the clustering and distribution of the physiologically relevant scaffold protein, PSD-95.During the formation of synapses, pre-and postsynaptic sides contain specific molecules that are involved in the regulation and plasticity of synaptic transmission (1-3). Although much is known about the molecular mechanisms of synaptic differentiation, major gaps remain in our understanding of the process, particularly with regard to the signals mediating the structuring of the postsynaptic apparatus of central mammalian synapses (2, 4). At excitatory synapses, the postsynaptic side is characterized by an electrodense thick matrix, called postsynaptic density (PSD).3 The PSD contains key molecules involved in the regulation of glutamate receptor targeting and trafficking (1, 5). There is considerable interest in elucidating the molecular mechanism that controls synaptic targeting and trafficking of these proteins in the postsynaptic region because of their essential role in synaptic plasticity (6). Moreover, in neurodegenerative pathologies, such as Alzheimer disease, it has been evidenced that the postsynaptic region, including several proteins of the PSD, is the primary target of the synaptotoxic effect of the amyloid ␤-peptide (7-9).Wnt signaling is essential for neuronal development and the maintenance of the nervous system (10 -12). Wnt regulates synapse formation; in fact, the pioneering work of Salinas and co-workers (12-15) established that Wnt-7a induces the clustering of presynaptic proteins in young primary cerebellar cultures. Also, Wnt ligands regulate neurogenesis of hippocampal stem cells in the adult rat (16), and Wnt-3a modulates long term potentiation in mouse hippocampal slices (17, 18).The expression of Wnt ligands and proteins of the Wnt signaling machinery in the matu...

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.

BackgroundSoluble amyloid-β (Aβ;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation.ResultsWe report here that the Wnt signaling activation prevents the synaptic damage triggered by Aβ oligomers. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic synaptic transmission in hippocampal slices indicates that Wnt-5a increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and both AMPA and NMDA components of the excitatory postsynaptic currents (EPSCs), without modifying the paired pulse facilitation (PPF). Conversely, in the presence of Aβ oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well. Co-perfusion of hippocampal slices with Wnt-5a and Aβ oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Aβ oligomers in neuronal cultures. Taken together these results indicate that Wnt-5a and Aβ oligomers inversely modulate postsynaptic components.ConclusionThese results indicate that post-synaptic damage induced by Aβ oligomers in hippocampal neurons is prevented by non-canonical Wnt pathway activation.