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Cell Rep. 2018 Jan 23;22(4):941-952. doi: 10.1016/j.celrep.2017.12.095. Epub 2018 Jan 28.

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

Author information

1
Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA 30329, USA.
2
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
3
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
4
Department of Biology, State University of New York, Albany, NY 12222, USA.
5
Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA 30329, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30329, USA. Electronic address: spapa@emory.edu.

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.

KEYWORDS:

AMPAR; NMDAR; Parkinson’s disease; SPN; dopamine; dyskinesia; glutamate; medium spiny neuron; striatal projection neuron; striatum

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