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Pathway-specific dysregulation of striatal excitatory synapses by LRRK2 mutations

Chen, Chuyu, Soto, Giulia, Dumrongprechachan, Vasin, Bannon, Nicholas, Kang, Shuo, Kozorovitskiy, Yevgenia, Parisiadou, Loukia·2020·eLife
DOI 10.7554/elife.58997PMC PMC7609054

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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.

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Metadata

Authors
Chen, C., Soto, G., Dumrongprechachan, V., Bannon, N., Kang, S., Kozorovitskiy, Y., & Parisiadou, L.
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2020-10-02
Volume
9
ISSN
2050-084X
DOI
10.7554/elife.58997
PMC
PMC7609054
Cited by
56
References
8
Language
en
Licence
Funders
  • National Institute of Neurological Disorders and Stroke (R01NS097901, R01NS107539, F32NS103243)
  • Michael J. Fox Foundation for Parkinson's Research (LRRK2 Challenge)
  • Rita Allen Foundation (Rita Allen Scholar Award)
  • Kinship Foundation (Searle Scholar Award)
  • Arnold and Mabel Beckman Foundation (Beckman Young Investigator Award)
  • American Heart Association (19PRE3438005)

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