Blunted mGluR Activation Disinhibits Striatopallidal Transmission in Parkinsonian Mice

Qiaoling Cui, Jason E. Pitt, Arin Pamukcu, Jean Francois Poulin, Omar S. Mabrouk, Michael P. Fiske, Isabel B. Fan, Elizabeth C. Augustine, Katherine A. Young, Robert T. Kennedy, Rajeshwar Awatramani, C. Savio Chan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The prevailing circuit model predicts that hyperactivity of the striatopallidal pathway and subsequently increased inhibition of external globus pallidus (GPe) neurons lead to the hypokinetic symptoms of Parkinson's disease (PD). It is believed that hyperactivity of the striatopallidal pathway is due to inactivity of dopamine receptors on the somatodendritic membrane of striatopallidal neurons, but the exact cellular underpinnings remain unclear. In this study, we show that mouse GPe astrocytes critically control ambient glutamate level, which in turn gates striatopallidal transmission via the activation of presynaptic metabotropic glutamate receptors. This presynaptic inhibition of striatopallidal transmission is diminished after the chronic loss of dopamine. Elevation of intracellular glutamate content in astrocytes restores the proper regulation of the striatopallidal input in PD models. These findings argue that astrocytes are key regulators of the striatopallidal synapse. Targeting this cell class may serve as an alternative therapeutic strategy for PD.

Original languageEnglish (US)
Pages (from-to)2431-2444
Number of pages14
JournalCell reports
Volume17
Issue number9
DOIs
StatePublished - Nov 22 2016

Keywords

  • 6-OHDA
  • GCaMP
  • astrocytes
  • basal ganglia
  • external globus pallidus
  • glutamate homeostasis
  • iGluSnFR
  • patch-clamp
  • striatum
  • tyrosine hydroxylase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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