Abstract
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.
Highlights
Received: 21 February 2021 Accepted: 19 April 2021 Published: 03 June 2021Citation: Galli S, Stancheva SH, Dufor T, Gibb AJ and Salinas PC (2021) Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling
We found that induced Dkk1 expression for 14 days led to the loss of 40% of inhibitory GABAergic synapses in the adult striatum accompanied by a decrease in the frequency of miniature inhibitory currents in D2-medium spiny neurons (MSNs)
We previously showed that blockade of endogenous Wnts through the inducible expression of Dkk1 results in the substantial loss of excitatory and dopaminergic synapses in the adult striatum without affecting cell viability (Galli et al, 2014)
Summary
Dkk expression triggers motor defects characteristic of striatal dysfunction (Galli et al, 2014), demonstrating a critical role of endogenous Wnt signaling in the maintenance of corticostriatal excitatory and dopaminergic synapses onto MSNs. the effect of Wnt deficiency on inhibitory synapses and whether these synaptic defects are reversible remain unknown. We demonstrate that cessation of Dkk results in normal motor coordination and the ability to respond to amphetamine These findings reveal the requirement of Wnt signaling for the maintenance of synaptic connections in the striatum and that reactivation of the Wnt pathway promotes the reassembly of functional neuronal circuits in this brain region.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
