Restoring neuron connections

The structural and functional integrity of synapses is crucial for neuronal circuit function and for the ability of animals to respond and adapt to their environment. However, synapses become dysfunctional or are lost in developmental and neurodegenerative disorders, and after brain and spinal cord injury (SCI). Deficiency in synapse integrity contributes to cognitive impairment and motor disability. To restore damaged neuronal circuits after SCI, antibody therapy against molecules such as Nogo, which inhibits axon growth, are in clinical trials (1). For other conditions such as Alzheimer's disease (AD), blockade of the pathogenic molecule amyloid-β or its downstream effects are being tested as potential therapies (2). To develop effective approaches for restoring impaired synapses, careful consideration should be given to the diversity of synaptogenic factors. To overcome this, on page 1074 of this issue, Suzuki et al. (3) report a structurally guided synthetic peptide to restore synaptic integrity of damaged and impaired circuits in mice

Postsynaptic assembly: A role for Wnt signalling

Synapse formation requires the coordinated formation of the presynaptic terminal, containing the machinery for neurotransmitter release, and the postsynaptic side that possesses the machinery for neurotransmitter reception. For coordinated pre- and postsynaptic assembly signals across the synapse are required. Wnt secreted proteins are well-known synaptogenic factors that promote the recruitment of presynaptic components in diverse organisms. However, recent studies demonstrate that Wnts act directly onto the postsynaptic side at both central and peripheral synapses to promote postsynaptic development and synaptic strength. This review focuses on the role of Wnts in postsynaptic development at central synapses and the neuromuscular junction. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013

Wnt-Frizzled Signaling Regulates Activity-Mediated Synapse Formation

The formation of synapses is a tightly regulated process that requires the coordinated assembly of the presynaptic and postsynaptic sides. Defects in synaptogenesis during development or in the adult can lead to neurodevelopmental disorders, neurological disorders, and neurodegenerative diseases. In order to develop therapeutic approaches for these neurological conditions, we must first understand the molecular mechanisms that regulate synapse formation. The Wnt family of secreted glycoproteins are key regulators of synapse formation in different model systems from invertebrates to mammals. In this review, we will discuss the role of Wnt signaling in the formation of excitatory synapses in the mammalian brain by focusing on Wnt7a and Wnt5a, two Wnt ligands that play an in vivo role in this process. We will also discuss how changes in neuronal activity modulate the expression and/or release of Wnts, resulting in changes in the localization of surface levels of Frizzled, key Wnt receptors, at the synapse. Thus, changes in neuronal activity influence the magnitude of Wnt signaling, which in turn contributes to activity-mediated synapse formation

A Role for Frizzled and Their Post-Translational Modifications in the Mammalian Central Nervous System

The Wnt pathway is a key signalling cascade that regulates the formation and function of neuronal circuits. The main receptors for Wnts are Frizzled (Fzd) that mediate diverse functions such as neurogenesis, axon guidance, dendritogenesis, synapse formation, and synaptic plasticity. These processes are crucial for the assembly of functional neuronal circuits required for diverse functions ranging from sensory and motor tasks to cognitive performance. Indeed, aberrant Wnt–Fzd signalling has been associated with synaptic defects during development and in neurodegenerative conditions such as Alzheimer’s disease. New studies suggest that the localisation and stability of Fzd receptors play a crucial role in determining Wnt function. Post-translational modifications (PTMs) of Fzd are emerging as an important mechanism that regulates these Wnt receptors. However, only phosphorylation and glycosylation have been described to modulate Fzd function in the central nervous system (CNS). In this review, we discuss the function of Fzd in neuronal circuit connectivity and how PTMs contribute to their function. We also discuss other PTMs, not yet described in the CNS, and how they might modulate the function of Fzd in neuronal connectivity. PTMs could modulate Fzd function by affecting Fzd localisation and stability at the plasma membrane resulting in local effects of Wnt signalling, a feature particularly important in polarised cells such as neurons. Our review highlights the importance of further studies into the role of PTMs on Fzd receptors in the context of neuronal connectivity

Dysfunction of Wnt signaling and synaptic disassembly in neurodegenerative diseases

The molecular mechanisms that regulate synapse formation have been well documented. However, little is known about the factors that modulate synaptic stability. Synapse loss is an early and invariant feature of neurodegenerative diseases including Alzheimer's (AD) and Parkinson's disease. Notably, in AD the extent of synapse loss correlates with the severity of the disease. Hence, understanding the molecular mechanisms that underlie synaptic maintenance is crucial to reveal potential targets that will allow the development of therapies to protect synapses. Wnts play a central role in the formation and function of neuronal circuits. Moreover, Wnt signaling components are expressed in the adult brain suggesting their role in synaptic maintenance in the adult. Indeed, blockade of Wnts with the Wnt antagonist Dickkopf-1 (Dkk1) causes synapse disassembly in mature hippocampal cells. Dkk1 is elevated in brain biopsies from AD patients and animal models. Consistent with these findings, Amyloid-β (Aβ) oligomers induce the rapid expression of Dkk1. Importantly, Dkk1 neutralizing antibodies protect synapses against Aβ toxicity, indicating that Dkk1 is required for Aβ-mediated synapse loss. In this review, we discuss the role of Wnt signaling in synapse maintenance in the adult brain, particularly in relation to synaptic loss in neurodegenerative diseases

Neurotrophin and Wnt signaling cooperatively regulate dendritic spine formation

Dendritic spines are major sites of excitatory synaptic transmission and changes in their numbers and morphology have been associated with neurodevelopmental and neurodegenerative disorders. Brain-derived Neurotrophic Factor (BDNF) is a secreted growth factor that influences hippocampal, striatal and neocortical pyramidal neuron dendritic spine density. However, the mechanisms by which BDNF regulates dendritic spines and how BDNF interacts with other regulators of spines remain unclear. We propose that one mechanism by which BDNF promotes dendritic spine formation is through an interaction with Wnt signaling. Here, we show that Wnt signaling inhibition in cultured cortical neurons disrupts dendritic spine development, reduces dendritic arbor size and complexity, and blocks BDNF-induced dendritic spine formation and maturation. Additionally, we show that BDNF regulates expression of Wnt2, and that Wnt2 is sufficient to promote cortical dendrite growth and dendritic spine formation. Together, these data suggest that BDNF and Wnt signaling cooperatively regulate dendritic spine formation

Deficient Wnt Signaling and Synaptic Vulnerability in Alzheimer's Disease: Emerging Roles for the LRP6 Receptor

Synapse dysfunction and loss represent critical early events in the pathophysiology of Alzheimer's disease (AD). While extensive research has elucidated the direct synaptotoxic effects of Amyloid-β (Aβ) oligomers, less is known about how signaling pathways at the synapse are affected by Aβ. A better understanding of the cellular and molecular mechanisms underlying synaptic vulnerability in AD is key to illuminating the determinants of AD susceptibility and will unveil novel therapeutic avenues. Canonical Wnt signaling through the Wnt co-receptor LRP6 has a critical role in maintaining the structural and functional integrity of synaptic connections in the adult brain. Accumulating evidence suggests that deficient Wnt signaling may contribute to AD pathology. In particular, LRP6 deficiency compromises synaptic function and stability, and contributes to Aß production and plaque formation. Here, we review the role of Wnt signaling for synaptic maintenance in the adult brain and the contribution of aberrant Wnt signaling to synaptic degeneration in AD. We place a focus on emerging evidence implicating the LRP6 receptor as an important modulator of AD risk and pathology

Wnt proteins as modulators of synaptic plasticity

Dynamic changes in the structure and function of synapses in response to the environment, termed synaptic plasticity, are the cellular basis of learning and memory. At excitatory synapses, activation of NMDA receptors by glutamate leads to calcium influx triggering intracellular pathways that promote the trafficking of AMPA receptors to the post-synaptic membrane and actin remodeling. New evidence shows that Wnt secreted proteins, known for their role in synapse development, are essential for early stages of long-term potentiation, a form of plasticity that increases synaptic strength. Here, we review recent progress in this area and the significance of Wnt signaling to synaptic plasticity in health and disease

C-Jun N-terminal kinase (JNK) cooperates with Gsk3 beta to regulate Dishevelled-mediated microtubule stability

Background: Wnt factors are a large family of signaling molecules that play important roles in the regulation of cell fate specification, tissue polarity and cell movement. In the nervous system, Wnts also regulates the formation of neuronal connection acting as retrograde signals that regulate the remodeling of the axons prior to the assembly of the presynaptic apparatus. The scaffold protein Dishevelled (Dvl) mimics the effect of Wnt on the neuronal cytoskeleton by increasing the number of stable microtubule along the axon shaft and inducing the formation of looped microtubules (MT) at enlarged growth cones. A divergent Wnt-Dvl canonical pathway which bifurcates downstream of Gsk3 beta regulates MT dynamics.Results: Here we show that the Wnt pathway also activates c-Jun N-terminal kinase (JNK) to regulate MT stabilization. Although in the Wnt planar cell polarity (PCP) pathway, JNK lays downstream of Rho GTPases, these GTPases are not required for Wnt-mediated MTs stability. Epistatic analyses and pharmacological studies suggest that the Wnt-Dvl signalling regulates the dynamic of the cytoskeleton through two different pathways that lead to inhibition of Gsk3 beta and activation of JNK in the same cell.Conclusion: We demonstrate a novel role for JNK in Wnt-mediated MT stability. Wnt-Dvl pathway increases MT stability through a transcription independent mechanism that requires the concomitant inhibition of Gsk3 beta and activation of JNK. These studies demonstrate that Wnts can simultaneously activate different signalling pathways to modulate cytoskeleton dynamics

Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling

Synapse degeneration in the striatum has been associated with the early stages of Parkinson’s and Huntington’s diseases (PD and HD). However, the molecular mechanisms that trigger synaptic dysfunction and loss are not fully understood. Increasing evidence suggests that deficiency in Wnt signaling triggers synapse degeneration in the adult brain and that this pathway is affected in neurodegenerative diseases. Here, we demonstrate that endogenous Wnt signaling is essential for the integrity of a subset of inhibitory synapses on striatal medium spiny neurons (MSNs). We found that inducible expression of the specific Wnt antagonist Dickkopf-1 (Dkk1) in the adult striatum leads to the loss of inhibitory synapses on MSNs and affects the synaptic transmission of D2-MSNs. We also discovered that re-activation of the Wnt pathway by turning off Dkk1 expression after substantial loss of synapses resulted in the complete recovery of GABAergic and dopamine synapse number. Our results also show that re-activation of the Wnt pathway leads to a recovery of amphetamine response and motor function. Our studies identify the Wnt signaling pathway as a potential therapeutic target for restoring neuronal circuits after synapse degeneration