Deficient Wnt signalling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice

Abstract

Synapse degeneration is an early and invariant feature of neurodegenerative diseases. Indeed, synapse loss occurs prior to neuronal degeneration and correlates with the symptom severity of these diseases. However, the molecular mechanisms that trigger synaptic loss remain poorly understood. Here we demonstrate that deficient Wnt signalling elicits synaptic degeneration in the adult striatum. Inducible expression of the secreted Wnt antagonist Dickkopf1 (Dkk1) in adult mice (iDkk1) decreases the number of cortico-striatal glutamatergic synapses and of D1 and D2 dopamine receptor clusters. Synapse loss occurs in the absence of axon retraction or cell death. The remaining excitatory terminals contain fewer synaptic vesicles and have a reduced probability of evoked transmitter release. IDkk1 mice show impaired motor coordination and are irresponsive to amphetamine. These studies identify Wnts as key endogenous regulators of synaptic maintenance and suggest that dysfunction in Wnt signalling contributes to synaptic degeneration at early stages in neurodegenerative diseases.

ALCAR Exerts Neuroprotective and Pro-Neurogenic Effects by Inhibition of Glial Activation and Oxidative Stress via Activation of the Wnt/β-Catenin Signaling in Parkinsonian Rats

“…Thus, we speculate that decreased glial activation and enhanced NSC and DAergic neuronal survival observed in our study could be due to decreased GSK-3β activation and increased β-catenin stabilization, indicating a role of ALCARmediated regulation of the Wnt/β-catenin pathway. Earlier studies suggested that the Wnt/β-catenin pathway stimulates selfrenewal of NSC and differentiation [55] towards neuronal phenotype by inhibiting gliogenesis [56], and down-regulation of this pathway causes striatal synaptic degeneration, resulting in impaired motor behaviour [57].…”

Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice

“…That these classic developmental cues may have critical functions in the adult brain has been implied by recent findings that broad-spectrum blockade or activation of Wnt pathway components affects synaptic structure, plasticity, and cognitive functions in adult animals (37)(38)(39)(40)(41). However, surprisingly little is known about which of the 19 vertebrate Wnts is essential for adult nervous system functions in vivo.…”

“…Previously, broad-spectrum Wnt antagonists have been shown to affect synaptic structure, plasticity, and cognitive functions in adult organisms (37)(38)(39)(40)(41). However, there are 19 vertebrate Wnts, and which Wnt is essential for these functions in the adult brain in vivo remains unknown.…”

The effects of gestational and chronic atrazine exposure on motor behaviors and striatal dopamine in male Sprague-Dawley rats

“…In rodents atrazine has been shown to alter locomotor activity (Bardullas et al, 2011; Belloni et al, 2011; Peruzovic et al, 1995; Rodriguez et al, 2013; Ugazio et al, 1991), delay righting reflexes (Belloni et al, 2011), and impair rotarod performance (Bardullas et al, 2011). These tasks have all been shown to measure behaviors that are controlled, in part, by NSDA neurons (Adeosun et al, 2012; Galli et al, 2014; Kravitz et al, 2010; Liu et al, 2014; Verhave et al, 2009; Yin et al, 2009). The walking beam assay assesses the ability of rats to traverse a narrow elevated beam and has proven to be very useful in the assessment of motor coordination (Goldsten, 2003).…”