Activity-dependent Synaptic Wnt Release Regulates Hippocampal Long Term Potentiation

Abstract

Wnts are important for various developmental and oncogenic processes. Here we show that Wnt signaling functions at synapses in hippocampal neurons. Tetanic stimulations induce N-methyl-Daspartate receptor-dependent synaptic Wnt3a release, nuclear ␤-catenin accumulations, and the activation of Wnt target genes. Suppression of Wnt signaling impairs long term potentiation. Conversely, activation of Wnt signaling facilitates long term potentiation. These findings suggest that Wnt signaling plays a critical role in regulating synaptic plasticity.Wnts are a family of secreted, lipid-modified signaling proteins that act as short range ligands to locally activate receptor-mediated signaling cascades. Wnt signaling is critical for a variety of developmental processes; its dysregulation is the causal factor for many diseases, especially cancer (1, 2). Wnt ligands bind to Frizzled receptors to activate intracellular signaling cascades, including the Wnt/␤-catenin, Wnt/Ca 2ϩ , and Wnt/planar cell polarity pathways (3). In the canonical Wnt/␤-catenin-signaling pathway, Frizzled receptors signal through Dishevelled to inhibit the kinase activity of glycogen synthase kinase 3␤ in a protein degradation complex containing Axin, ␤-catenin, and other proteins. When Wnt signaling is inactive, ␤-catenin is phosphorylated by glycogen synthase kinase 3␤ and thus rapidly degraded via the proteosome pathway; the activation of Wnt signaling stabilizes ␤-catenin by inhibiting glycogen synthase kinase 3␤. Stabilized ␤-catenin translocates to the nuclei and binds the TCF/LEF family of transcription factors to regulate the expression of Wnt target genes (1, 2). In addition, ␤-catenin is a component of the cadherin complex and plays an important role in regulating cell-cell adhesion (4). Among many Wnt-regulated developmental processes are neural patterning and differentiation (5), including hippocampal formation (6 -8), dendritic morphogenesis (9, 10), axon guidance (11-16), and synapse formation (11,17,18).Wnts are expressed in the brain (19 -21). Dysregulation of Wnt signaling has been suggested as an etiological cause for specific mental disorders. For example, Wnt signaling is up-regulated in schizophrenic brains (22)(23)(24). Several studies suggested an association of Frizzled-3 with schizophrenic susceptibility (25-27). On the other hand, downregulation of the Wnt/␤-catenin pathway is implicated in Alzheimer disease etiology (28 -34). A recent study indicated that cocaine exposures affect the expression of many Wnt signal-related genes (35). In addition, mutation of Dishevelled-1 in mice produces behavioral impairments (36), whereas mutation of a Drosophila Wnt receptor, Derailed (13), causes memory deficits (37, 38). Collectively, available data point to the role of Wnt signaling in the modulation of brain functions. However, the mechanism by which Wnt signaling regulates brain function is completely unknown.Here we report the synaptic localization of Wnt signaling proteins in mouse hippocampal neurons, the activity-induced Wnt3a rel...

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.…”

The ups and downs of Wnt signaling in prevalent neurological disorders

“…Intriguingly, loss of function of either TSC1 or TSC2 trigger an enlargement of somas and dendritic spines and alter the properties of functional synapses in postmitotic hippocampal neurons (Tavazoie et al, 2005). It remains to be studied whether neuronal deregulation of TSC1/2 augment b-catenin signaling activity thus affecting neuronal plasticity, a phenomenon which is increasingly recognized to be dependent, at least in part, on the normal activity of Wnt signaling components (Salinas, 1999(Salinas, , 2005Packard et al, 2002;Wang et al, 2003;Chen et al, 2006). Third, twin and family studies have provided compelling evidence for a strong genetic component among autistic individuals (Folstein et al, 2003;Hu-Lince et al, 2005;Vorstman et al, 2006).…”

Wnts: up-and-coming at the synapse

“…Two recent studies support this view [12,31]. Electrophysiological recordings in cerebellar slices from Wnt7a −/− -Dvl1 −/− P14-P15 mice revealed a significant decrease in miniature excitatory postsynaptic current frequency at the MF-GC synapse.…”

“…To identify molecular pathways underlying L-LTP, a microarray analysis of dentate gyrus slice preparations, in which LTP had been induced, was performed [31]. Notably, multiple Wnt signaling players were identified [31].…”

“…To identify molecular pathways underlying L-LTP, a microarray analysis of dentate gyrus slice preparations, in which LTP had been induced, was performed [31]. Notably, multiple Wnt signaling players were identified [31]. Furthermore, punctate WNT-3a and Frizzled-4 staining, both of which colocalized with the postsynaptic protein PSD-95, were found in the molecular layer of the dentate gyrus.…”