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Author Notes:

Correspondence: spapa@emory.edu

AUTHOR CONTRIBUTIONS: Design and Conceptualization, S.F.T. and S.M.P.; Investigation, A.S., M.A.J., K.J.B., and G.B.; Analysis, A.S., M.A.J, A.J., A.S., S.F.T., and S.M.P.; Writing, A.S., M.A.J., A.J., A.S., S.F.T., and S.M.P.; Review and Editing, A.S., M.A.J., K.J.B., G.B., A.J., A.S., S.F.T., and S.M.P.

We thank Dr. Yoland Smith for advice on histological parameters and Bhagya Dyavar Shetty for technical assistance in the production and care of the primate model with advanced PD.

DECLARATION OF INTERESTS: The authors declare no competing interests.

Subjects:

Research Funding:

This work was supported by NIH grants NS045962 and NS073994 (S.M.P.) and NS036654 and NS065371 (S.F.T.); SUNY Albany Research Foundation, and National Science Foundation (NSF) grant IOS1655365 (A.S.); and National Center for Research Resources (NCRR) grant RR000165 and Office of Research Infrastructure Programs (ORIP)/OD grant OD011132 (Yerkes National Primate Research Center).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • LEVODOPA-INDUCED DYSKINESIAS
  • MEDIUM SPINY NEURONS
  • SYNAPTIC PLASTICITY
  • BASAL GANGLIA
  • STRIATOPALLIDAL NEURONS
  • INDIRECT PATHWAYS
  • DISEASE
  • SYNAPSES
  • MODELS
  • ANTAGONIST

Glutamatergic Tuning of Hyperactive Striatal Projection Neurons Controls the Motor Response to Dopamine Replacement in Parkinsonian Primates

Tools:

Journal Title:

Cell Reports

Volume:

Volume 22, Number 4

Publisher:

, Pages 941-952

Type of Work:

Article | Final Publisher PDF

Abstract:

Dopamine (DA) loss in Parkinson's disease (PD) alters the function of striatal projection neurons (SPNs) and causes motor deficits, but DA replacement can induce further abnormalities. A key pathological change in animal models and patients is SPN hyperactivity; however, the role of glutamate in altered DA responses remains elusive. We tested the effect of locally applied AMPAR or NMDAR antagonists on glutamatergic signaling in SPNs of parkinsonian primates. Following a reduction in basal hyperactivity by antagonists at either receptor, DA inputs induced SPN firing changes that were stable during the entire motor response, in clear contrast with the typically unstable effects. The SPN activity reduction over an extended putamenal area controlled the release of involuntary movements in the "on" state and therefore improved motor responses to DA replacement. These results demonstrate the pathophysiological role of upregulated SPN activity and support strategies to reduce striatal glutamate signaling for PD therapy.

Copyright information:

© 2017 The Author(s).

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