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Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations
LRRK2 is a kinase expressed in striatal spiny projection neurons (SPNs), cells which lose dopaminergic input in Parkinson’s disease (PD). R1441C and G2019S are the most common pathogenic mutations of LRRK2. How these mutations alter the structure and function of individual synapses on direct and ind...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609054/ https://www.ncbi.nlm.nih.gov/pubmed/33006315 http://dx.doi.org/10.7554/eLife.58997 |
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author | Chen, Chuyu Soto, Giulia Dumrongprechachan, Vasin Bannon, Nicholas Kang, Shuo Kozorovitskiy, Yevgenia Parisiadou, Loukia |
author_facet | Chen, Chuyu Soto, Giulia Dumrongprechachan, Vasin Bannon, Nicholas Kang, Shuo Kozorovitskiy, Yevgenia Parisiadou, Loukia |
author_sort | Chen, Chuyu |
collection | PubMed |
description | LRRK2 is a kinase expressed in striatal spiny projection neurons (SPNs), cells which lose dopaminergic input in Parkinson’s disease (PD). R1441C and G2019S are the most common pathogenic mutations of LRRK2. How these mutations alter the structure and function of individual synapses on direct and indirect pathway SPNs is unknown and may reveal pre-clinical changes in dopamine-recipient neurons that predispose toward disease. Here, R1441C and G2019S knock-in mice enabled thorough evaluation of dendritic spines and synapses on pathway-identified SPNs. Biochemical synaptic preparations and super-resolution imaging revealed increased levels and altered organization of glutamatergic AMPA receptors in LRRK2 mutants. Relatedly, decreased frequency of miniature excitatory post-synaptic currents accompanied changes in dendritic spine nano-architecture, and single-synapse currents, evaluated using two-photon glutamate uncaging. Overall, LRRK2 mutations reshaped synaptic structure and function, an effect exaggerated in R1441C dSPNs. These data open the possibility of new neuroprotective therapies aimed at SPN synapse function, prior to disease onset. |
format | Online Article Text |
id | pubmed-7609054 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-76090542020-11-04 Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations Chen, Chuyu Soto, Giulia Dumrongprechachan, Vasin Bannon, Nicholas Kang, Shuo Kozorovitskiy, Yevgenia Parisiadou, Loukia eLife Neuroscience LRRK2 is a kinase expressed in striatal spiny projection neurons (SPNs), cells which lose dopaminergic input in Parkinson’s disease (PD). R1441C and G2019S are the most common pathogenic mutations of LRRK2. How these mutations alter the structure and function of individual synapses on direct and indirect pathway SPNs is unknown and may reveal pre-clinical changes in dopamine-recipient neurons that predispose toward disease. Here, R1441C and G2019S knock-in mice enabled thorough evaluation of dendritic spines and synapses on pathway-identified SPNs. Biochemical synaptic preparations and super-resolution imaging revealed increased levels and altered organization of glutamatergic AMPA receptors in LRRK2 mutants. Relatedly, decreased frequency of miniature excitatory post-synaptic currents accompanied changes in dendritic spine nano-architecture, and single-synapse currents, evaluated using two-photon glutamate uncaging. Overall, LRRK2 mutations reshaped synaptic structure and function, an effect exaggerated in R1441C dSPNs. These data open the possibility of new neuroprotective therapies aimed at SPN synapse function, prior to disease onset. eLife Sciences Publications, Ltd 2020-10-02 /pmc/articles/PMC7609054/ /pubmed/33006315 http://dx.doi.org/10.7554/eLife.58997 Text en © 2020, Chen et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Neuroscience Chen, Chuyu Soto, Giulia Dumrongprechachan, Vasin Bannon, Nicholas Kang, Shuo Kozorovitskiy, Yevgenia Parisiadou, Loukia Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations |
title | Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations |
title_full | Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations |
title_fullStr | Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations |
title_full_unstemmed | Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations |
title_short | Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations |
title_sort | pathway-specific dysregulation of striatal excitatory synapses by lrrk2 mutations |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609054/ https://www.ncbi.nlm.nih.gov/pubmed/33006315 http://dx.doi.org/10.7554/eLife.58997 |
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