Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations

Chuyu Chen, Giulia Soto, Vasin Dumrongprechachan, Nicholas Bannon, Shuo Kang, Yevgenia Kozorovitskiy*, Loukia Parisiadou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 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.

Original languageEnglish (US)
Article numbere58997
Pages (from-to)1-26
Number of pages26
JournaleLife
Volume9
DOIs
StatePublished - Oct 2020

Funding

This work was supported by Michael J Fox Foundation for Parkinson’s Research (LP), NIH R01 NS097901 (LP), NINDS R01 NS107539 (YK), Rita Allen Foundation Scholar Award (YK), Searle Scholar Award (YK), and Beckman Young Investigator Award (YK). NB was supported by NINDS F32 NS103243 and VD by a predoctoral award from the American Heart Association (19PRE34380056). SIM imaging was performed at the Center for Advanced Microcopy, Northwestern University, supported by the NIH 1S10OD016342-01 and NCI CCSG P30 CA060553. The authors are grateful to Lindsey Butler for mouse colony management. We also thank Dr. Heather Melrose for providing the LRRK2 G2019S knock-in mice. 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 Neurolo-gical 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 Beckman Young Yevgenia Kozorovitskiy National Institute of Neurolo-gical Disorders and Stroke F32NS103243 Nicholas Bannon American Heart Association 19PRE3438005 Vasin Dumrongprechachan The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. This work was supported by Michael J Fox Foundation for Parkinson’s Research (LP), NIH R01 NS097901 (LP), NINDS R01 NS107539 (YK), Rita Allen Foundation Scholar Award (YK), Searle Scholar Award (YK), and Beckman Young Investigator Award (YK). NB was supported by NINDS F32 NS103243 and VD by a predoctoral award from the American Heart Association (19PRE34380056). SIM imaging was performed at the Center for Advanced Microcopy, Northwestern University, supported by the NIH 1S10OD016342-01 and NCI CCSG P30 CA060553. The authors are grateful to Lindsey Butler for mouse colony management. We also thank Dr. Heather Melrose for providing the LRRK2 G2019S knock-in mice.

ASJC Scopus subject areas

  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology
  • General Neuroscience

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