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

Galli, S; Stancheva, SH; Dufor, T; Gibb, AJ; Salinas, PC; (2021) Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling. Frontiers in Synaptic Neuroscience , 13 , Article 670467. 10.3389/fnsyn.2021.670467. Green open access

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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.

Type: Article
Title: Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fnsyn.2021.670467
Publisher version: https://doi.org/10.3389/fnsyn.2021.670467
Language: English
Additional information: © 2021 Galli, Stancheva, Dufor, Gibb and Salinas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Keywords: synapse degeneration, Dkk1, neuronal circuit restoration, medium spiny neurons, neurodegenerative disease
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10129913
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