Loss of Hyperdirect Pathway Cortico-Subthalamic Inputs Following Degeneration of Midbrain Dopamine Neurons

Hong Yuan Chu, Eileen L. McIver, Ryan F. Kovaleski, Jeremy F. Atherton, Mark D. Bevan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

81 Scopus citations


The motor symptoms of Parkinson's disease (PD) are linked to abnormally correlated and coherent activity in the cortex and subthalamic nucleus (STN). However, in parkinsonian mice we found that cortico-STN transmission strength had diminished by 50%–75% through loss of axo-dendritic and axo-spinous synapses, was incapable of long-term potentiation, and less effectively patterned STN activity. Optogenetic, chemogenetic, genetic, and pharmacological interrogation suggested that downregulation of cortico-STN transmission in PD mice was triggered by increased striato-pallidal transmission, leading to disinhibition of the STN and increased activation of STN NMDA receptors. Knockdown of STN NMDA receptors, which also suppresses proliferation of GABAergic pallido-STN inputs in PD mice, reduced loss of cortico-STN transmission and patterning and improved motor function. Together, the data suggest that loss of dopamine triggers a maladaptive shift in the balance of synaptic excitation and inhibition in the STN, which contributes to parkinsonian activity and motor dysfunction. Chu et al. report that, following loss of dopamine, activation of subthalamic nucleus (STN) NMDA receptors triggers a maladaptive reduction in cortico-STN transmission.

Original languageEnglish (US)
Pages (from-to)1306-1318.e5
Issue number6
StatePublished - Sep 13 2017


  • NMDA
  • Parkinson's disease
  • basal ganglia
  • cortex
  • globus pallidus
  • glutamate
  • plasticity
  • subthalamic nucleus
  • synapse

ASJC Scopus subject areas

  • General Neuroscience


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