Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Chuyu, Soto, Giulia, Dumrongprechachan, Vasin, Bannon, Nicholas, Kang, Shuo, Kozorovitskiy, Yevgenia, Parisiadou, Loukia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
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
_version_ 1783604945379917824
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
work_keys_str_mv AT chenchuyu pathwayspecificdysregulationofstriatalexcitatorysynapsesbylrrk2mutations
AT sotogiulia pathwayspecificdysregulationofstriatalexcitatorysynapsesbylrrk2mutations
AT dumrongprechachanvasin pathwayspecificdysregulationofstriatalexcitatorysynapsesbylrrk2mutations
AT bannonnicholas pathwayspecificdysregulationofstriatalexcitatorysynapsesbylrrk2mutations
AT kangshuo pathwayspecificdysregulationofstriatalexcitatorysynapsesbylrrk2mutations
AT kozorovitskiyyevgenia pathwayspecificdysregulationofstriatalexcitatorysynapsesbylrrk2mutations
AT parisiadouloukia pathwayspecificdysregulationofstriatalexcitatorysynapsesbylrrk2mutations