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Cell- and state-specific plasticity of striatal glutamatergic synapses is critical to the expression of levodopa-induced dyskinesia

Shen, Weixing ; Zhai, Shenyu ; Francardo, Veronica LU ; Cui, Qiaoling ; Sun, Linqing ; Xie, Zhong ; Tkatch, Tatiana ; Corredor, Valeria Estrada ; Lein, Edward S and Ting, Jonathan T , et al. (2026) In Neuron 114(11). p.3-2019
Abstract

Levodopa-induced dyskinesia (LID) is a debilitating complication of symptomatic therapy in Parkinson's disease. Although there is compelling evidence that striatal pathophysiology is a major driver of LID, the specific circuit mechanisms governing its expression remain obscure. To address this gap, molecular, cellular, and behavioral strategies were used to interrogate circuits in a mouse model of LID. These studies revealed that LID induction led to an upregulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) in indirect pathway spiny projection neurons (iSPNs), the emergence of "silent" glutamatergic synapses, and long-term synaptic potentiation. Knocking down the expression of Grin2b mRNA in iSPNs dramatically... (More)

Levodopa-induced dyskinesia (LID) is a debilitating complication of symptomatic therapy in Parkinson's disease. Although there is compelling evidence that striatal pathophysiology is a major driver of LID, the specific circuit mechanisms governing its expression remain obscure. To address this gap, molecular, cellular, and behavioral strategies were used to interrogate circuits in a mouse model of LID. These studies revealed that LID induction led to an upregulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) in indirect pathway spiny projection neurons (iSPNs), the emergence of "silent" glutamatergic synapses, and long-term synaptic potentiation. Knocking down the expression of Grin2b mRNA in iSPNs dramatically attenuated both the development and expression of LID without compromising the beneficial effects of levodopa on movement. Taken together, these studies demonstrate that dyskinesiogenic doses of levodopa trigger cell-specific synaptic adaptations that are necessary for the network pathophysiology underlying LID and suggest that targeting GluN2B-containing NMDARs in iSPNs could be therapeutically useful.

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type
Contribution to journal
publication status
published
subject
keywords
Animals, Levodopa/adverse effects, Receptors, N-Methyl-D-Aspartate/metabolism, Dyskinesia, Drug-Induced/metabolism, Synapses/drug effects, Neuronal Plasticity/physiology, Corpus Striatum/drug effects, Mice, Antiparkinson Agents/adverse effects, Medium Spiny Neurons, Glutamic Acid/metabolism, Male
in
Neuron
volume
114
issue
11
pages
3 - 2019
publisher
Cell Press
external identifiers
  • pmid:42086052
  • scopus:105037743057
ISSN
0896-6273
DOI
10.1016/j.neuron.2026.04.023
language
English
LU publication?
yes
additional info
Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.
id
9f6694f2-0056-4c04-addc-5d05231f1f7f
date added to LUP
2026-06-16 09:06:41
date last changed
2026-07-16 12:46:47
@article{9f6694f2-0056-4c04-addc-5d05231f1f7f,
  abstract     = {{<p>Levodopa-induced dyskinesia (LID) is a debilitating complication of symptomatic therapy in Parkinson's disease. Although there is compelling evidence that striatal pathophysiology is a major driver of LID, the specific circuit mechanisms governing its expression remain obscure. To address this gap, molecular, cellular, and behavioral strategies were used to interrogate circuits in a mouse model of LID. These studies revealed that LID induction led to an upregulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) in indirect pathway spiny projection neurons (iSPNs), the emergence of "silent" glutamatergic synapses, and long-term synaptic potentiation. Knocking down the expression of Grin2b mRNA in iSPNs dramatically attenuated both the development and expression of LID without compromising the beneficial effects of levodopa on movement. Taken together, these studies demonstrate that dyskinesiogenic doses of levodopa trigger cell-specific synaptic adaptations that are necessary for the network pathophysiology underlying LID and suggest that targeting GluN2B-containing NMDARs in iSPNs could be therapeutically useful.</p>}},
  author       = {{Shen, Weixing and Zhai, Shenyu and Francardo, Veronica and Cui, Qiaoling and Sun, Linqing and Xie, Zhong and Tkatch, Tatiana and Corredor, Valeria Estrada and Lein, Edward S and Ting, Jonathan T and Cenci, M Angela and Surmeier, D James}},
  issn         = {{0896-6273}},
  keywords     = {{Animals; Levodopa/adverse effects; Receptors, N-Methyl-D-Aspartate/metabolism; Dyskinesia, Drug-Induced/metabolism; Synapses/drug effects; Neuronal Plasticity/physiology; Corpus Striatum/drug effects; Mice; Antiparkinson Agents/adverse effects; Medium Spiny Neurons; Glutamic Acid/metabolism; Male}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{11}},
  pages        = {{3--2019}},
  publisher    = {{Cell Press}},
  series       = {{Neuron}},
  title        = {{Cell- and state-specific plasticity of striatal glutamatergic synapses is critical to the expression of levodopa-induced dyskinesia}},
  url          = {{http://dx.doi.org/10.1016/j.neuron.2026.04.023}},
  doi          = {{10.1016/j.neuron.2026.04.023}},
  volume       = {{114}},
  year         = {{2026}},
}