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

• Type of Material: Article
• Authors: Arun Singh, Emory University; Meagan A. Jenkins, Emory University; Kenneth J. Burke, Emory University; Goichi Beck, Emory University; Andrew Jenkins, Emory University; Annalisa Scimemi, State University of New York; Stephen Traynelis, Emory University; Stella Papa, Emory University
• Language: English
• Date: 2018-01-23
• Publisher: Elsevier (Cell Press): OAJ
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Author(s).
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2017.12.095
• Title of Journal or Parent Work: Cell Reports
• ISSN: 2211-1247
• Volume: 22
• Issue: 4
• Start Page: 941
• End Page: 952
• Grant/Funding Information: 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: BASAL GANGLIA; MEDIUM SPINY NEURONS; ANTAGONIST; MODELS; STRIATOPALLIDAL NEURONS; INDIRECT PATHWAYS; Cell Biology; LEVODOPA-INDUCED DYSKINESIAS; Life Sciences & Biomedicine; SYNAPTIC PLASTICITY; DISEASE; Science & Technology; SYNAPSES
• Research Categories: Biology, Neuroscience; Health Sciences, Pharmacology

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.