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

Ávila, Miguel E.; Sepúlveda, Fernando J.; Burgos, Carlos F.; Moraga-Cid, Gustavo; Parodí, Jorge; Moon, Randall T.; Aguayo, Luis G.; Opazo, Carlos; Ferrari, Giancarlo V. De

doi:10.1074/jbc.m110.103028

Cited by 63 publications

(63 citation statements)

References 42 publications

(57 reference statements)

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“…Taken together, our findings suggest that Wnt-5a signaling through the Wnt/Ca 2+ pathway modulates spine morphogenesis and synaptic function. A recent study indicated that Wnt-3a is able to induce an increase both in the intracellular calcium concentration and in the frequency of mEPSC (35). These changes probably are related to the presynaptic release of neurotransmitter, a result consistent with our earlier studies showing that Wnt-3a modulates the recycling of synaptic vesicles in hippocampal synapses (12).…”

Section: Discussionsupporting

confidence: 81%

Wingless-type family member 5A (Wnt-5a) stimulates synaptic differentiation and function of glutamatergic synapses

Varela-Nallar

Alfaro

Serrano

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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196

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Growing evidence indicates that Wingless-type (Wnt) signaling plays an important role in the maturation of the central nervous system. We report here that Wingless-type family member 5A (Wnt-5a) is expressed early in development and stimulates dendrite spine morphogenesis, inducing de novo formation of spines and increasing the size of the preexisting ones in hippocampal neurons. Wnt-5a increased intracellular calcium concentration in dendritic processes and the amplitude of NMDA spontaneous miniature currents. Acute application of Wnt-5a increased the amplitude of field excitatory postsynaptic potentials (fEPSP) in hippocampal slices, an effect that was prevented by calciumchannel blockers. The physiological relevance of our findings is supported by studies showing that Wnt scavengers decreased spine density, miniature excitatory postsynaptic currents, and fEPSP amplitude. We conclude that Wnt-5a stimulates different aspects of synaptic differentiation and plasticity in the mammalian central nervous system.T he Wingless-type (Wnt) signaling pathway modulates several developmental processes, and it is activated by the interaction of the Wnt ligand with members of the Frizzled (Fz) family of seven transmembrane cell-surface receptors (1). It has been reported that Wnt signaling plays a key role in diverse aspects of neuronal development and connectivity (2), regulating axon guidance and remodeling (3), dendrite development (4), synapse formation, (5) and synaptic plasticity (6, 7). Several components of the Wnt pathway are localized at adult synapses, indicating that the molecular machinery required to transduce Wnt signaling is structurally localized at central synapses (8). Different pathways have been described downstream of Fz receptors: the canonical Wnt/β-catenin pathway and the noncanonical ones which involve intracellular signaling by Ca 2+ (the Wnt/Ca 2+ pathway) and the JNK cascade (the Wnt/JNK pathway) (9, 10). Different canonical Wnt ligands have been shown to modulate the presynaptic region. Wnt-7a increases the clustering of synapsin 1 in cerebellar neurons (3) and regulates the trafficking of the α 7 nicotinic acetylcholine receptor to presynaptic terminals in hippocampal neurons (11). In addition, double-mutant mice lacking Wnt-7a and Dishevelled 1 show impaired neurotransmitter release at existing synapses, suggesting a role for Wnt signaling in synaptic transmission (5). Wnt-7a and Wnt-3a were shown to induce the recycling and exocytosis of synaptic vesicles in mature hippocampal neurons and to enhance synaptic transmission in adult hippocampal slices (12). Wnt7a/b levels also were increased in CA3 pyramidal neurons by an enriched environment in which the increase in synapse number at the hippocampal stratum lucidum was shown to be mediated by Wnt signaling (13). Wnt-3a is able to modulate presynaptic differentiation (14,15), and it is released from synapses by an activity-dependent mechanism that facilitates postsynaptic long-term potentiation (6).Recent studies indicated that a different Wnt l...

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Section: Discussionsupporting

confidence: 81%

Wingless-type family member 5A (Wnt-5a) stimulates synaptic differentiation and function of glutamatergic synapses

Varela-Nallar

Alfaro

Serrano

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

196

203

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“…Our result showed that a close linkage was observed between signaling pathways identified and MDD, as shown in Table 1. For instance, Wnt signaling pathway played a role in neurogenesis, synapse formation, synapse transmission, and dendritic arborization in hippocampus (Avila et al, 2010;Gogolla et al, 2009;Vanderhaeghen, 2009;Wayman et al, 2006), and disruption of canonical Wnt/Fz/GSK3 signaling had been associated with various neurodevelopmental and neuropsychiatric disorders, including major affective disorders (Inestrosa and Arenas, 2010). mTOR signaling, particularly via p70S6K/eIF4B pathway, participated in the pathophysiology of depression and antidepressive activity (Jernigan et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of microRNA in peripheral blood mononuclear cells as specific biomarker for major depressive disorder patients

Fan

Sun

Guo

et al. 2014

Journal of Psychiatric Research

113

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“…56,57,59,66,67 β-Catenin functions presynaptically to enhance mEPSC frequency, with no change in evoked release, via its role in regulating the localization and release of specific synaptic vesicle pools, independent of Wnt-induced transcription. 68 …”

Section: Discussionmentioning

confidence: 99%

Adenomatous polyposis coli protein deletion leads to cognitive and autism-like disabilities

Alexander

Pirone

et al. 2014

Mol Psychiatry

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Intellectual disabilities (IDs) and autism spectrum disorders link to human APC inactivating gene mutations. However, little is known about adenomatous polyposis coli’s (APC’s) role in the mammalian brain. This study is the first direct test of the impact of APC loss on central synapses, cognition and behavior. Using our newly generated APC conditional knock-out (cKO) mouse, we show that deletion of this single gene in forebrain neurons leads to a multisyndromic neurodevelopmental disorder. APC cKO mice, compared with wild-type littermates, exhibit learning and memory impairments, and autistic-like behaviors (increased repetitive behaviors, reduced social interest). To begin to elucidate neuronal changes caused by APC loss, we focused on the hippocampus, a key brain region for cognitive function. APC cKO mice display increased synaptic spine density, and altered synaptic function (increased frequency of miniature excitatory synaptic currents, modestly enhanced long-term potentiation). In addition, we found excessive β-catenin levels and associated changes in canonical Wnt target gene expression and N-cadherin synaptic adhesion complexes, including reduced levels of presenilin1. Our findings identify some novel functional and molecular changes not observed previously in other genetic mutant mouse models of co-morbid cognitive and autistic-like disabilities. This work thereby has important implications for potential therapeutic targets and the impact of their modulation. We provide new insights into molecular perturbations and cell types that are relevant to human ID and autism. In addition, our data elucidate a novel role for APC in the mammalian brain as a hub that links to and regulates synaptic adhesion and signal transduction pathways critical for normal cognition and behavior.

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

Cited by 63 publications

References 42 publications

Wingless-type family member 5A (Wnt-5a) stimulates synaptic differentiation and function of glutamatergic synapses

Wingless-type family member 5A (Wnt-5a) stimulates synaptic differentiation and function of glutamatergic synapses

Differential expression of microRNA in peripheral blood mononuclear cells as specific biomarker for major depressive disorder patients

Adenomatous polyposis coli protein deletion leads to cognitive and autism-like disabilities

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