Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations
- Feinberg School of Medicine, Northwestern University, United States
- Northwestern University, United States
Abstract
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 towards 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 2-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.
Data availability
All data generated during this study are included in the manuscript and supporting files.
Article and author information
Author details
Yevgenia Kozorovitskiy
Funding
National Institute of Neurological Disorders and Stroke (R01NS097901)
- Loukia Parisiadou
Michael J. Fox Foundation for Parkinson's Research (LRRK2 Challenge)
- Loukia Parisiadou
National Institute of Neurological Disorders and Stroke (R01NS107539)
- Yevgenia Kozorovitskiy
Rita Allen Foundation (Rita Allen Scholar Award)
- Yevgenia Kozorovitskiy
Kinship Foundation (Searle Scholar Award)
- Yevgenia Kozorovitskiy
Arnold and Mabel Beckman Foundation (Beckman Young Investigator Award)
- Yevgenia Kozorovitskiy
National Institute of Neurological Disorders and Stroke (F32NS103243)
- Nicholas Bannon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Carl Lupica
Ethics
Animal experimentation: All mouse experiments were approved by Northwestern University Animal Care and Use Committee (Approved protocol numbers IS000035451, IS00000838, and 00009022).
Version history
- Received: May 16, 2020
- Accepted: October 1, 2020
- Accepted Manuscript published: October 2, 2020 (version 1)
- Version of Record published: November 3, 2020 (version 2)
Copyright
© 2020, Chen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations
eLife 9:e58997.
https://doi.org/10.7554/eLife.58997
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