Maladaptive Downregulation of Autonomous Subthalamic Nucleus Activity following the Loss of Midbrain Dopamine Neurons

Eileen L. McIver, Jeremy F. Atherton, Hongyuan Chu, Kathleen E. Cosgrove, Jyothisri Kondapalli, David Wokosin, D. James Surmeier, Mark D. Bevan*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Abnormal subthalamic nucleus (STN) activity is linked to impaired movement in Parkinson's disease (PD). The autonomous firing of STN neurons, which contributes to their tonic excitation of the extrastriatal basal ganglia and shapes their integration of synaptic input, is downregulated in PD models. Using electrophysiological, chemogenetic, genetic, and optical approaches, we find that chemogenetic activation of indirect pathway striatopallidal neurons downregulates intrinsic STN activity in normal mice but this effect is occluded in Parkinsonian mice. Loss of autonomous spiking in PD mice is prevented by STN N-methyl-D-aspartate receptor (NMDAR) knockdown and reversed by reactive oxygen species breakdown or KATP channel inhibition. Chemogenetic activation of hM3D(Gq) in STN neurons in Parkinsonian mice rescues their intrinsic activity, modifies their synaptic integration, and ameliorates motor dysfunction. Together these data argue that in PD mice increased indirect pathway activity leads to disinhibition of the STN, which triggers maladaptive NMDAR-dependent downregulation of autonomous firing.

Original languageEnglish (US)
Pages (from-to)992-1002.e4
JournalCell reports
Volume28
Issue number4
DOIs
StatePublished - Jul 23 2019

Keywords

  • akinesia
  • bradykinesia
  • decorrelated
  • globus pallidus
  • glutamatergic
  • hydrogen peroxide
  • hyperdirect pathway
  • indirect pathway
  • mitochondria
  • striatum

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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