Cargando…
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 tr...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209303/ https://www.ncbi.nlm.nih.gov/pubmed/34149390 http://dx.doi.org/10.3389/fnsyn.2021.670467 |
_version_ | 1783709099148443648 |
---|---|
author | Galli, Soledad Stancheva, Stefka H. Dufor, Tom Gibb, Alasdair J. Salinas, Patricia C. |
author_facet | Galli, Soledad Stancheva, Stefka H. Dufor, Tom Gibb, Alasdair J. Salinas, Patricia C. |
author_sort | Galli, Soledad |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8209303 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82093032021-06-18 Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling Galli, Soledad Stancheva, Stefka H. Dufor, Tom Gibb, Alasdair J. Salinas, Patricia C. Front Synaptic Neurosci Neuroscience 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. Frontiers Media S.A. 2021-06-03 /pmc/articles/PMC8209303/ /pubmed/34149390 http://dx.doi.org/10.3389/fnsyn.2021.670467 Text en Copyright © 2021 Galli, Stancheva, Dufor, Gibb and Salinas. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Galli, Soledad Stancheva, Stefka H. Dufor, Tom Gibb, Alasdair J. Salinas, Patricia C. Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling |
title | Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling |
title_full | Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling |
title_fullStr | Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling |
title_full_unstemmed | Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling |
title_short | Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling |
title_sort | striatal synapse degeneration and dysfunction are reversed by reactivation of wnt signaling |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209303/ https://www.ncbi.nlm.nih.gov/pubmed/34149390 http://dx.doi.org/10.3389/fnsyn.2021.670467 |
work_keys_str_mv | AT gallisoledad striatalsynapsedegenerationanddysfunctionarereversedbyreactivationofwntsignaling AT stanchevastefkah striatalsynapsedegenerationanddysfunctionarereversedbyreactivationofwntsignaling AT dufortom striatalsynapsedegenerationanddysfunctionarereversedbyreactivationofwntsignaling AT gibbalasdairj striatalsynapsedegenerationanddysfunctionarereversedbyreactivationofwntsignaling AT salinaspatriciac striatalsynapsedegenerationanddysfunctionarereversedbyreactivationofwntsignaling |