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

Neuron. 2017 Sep 13;95(6):1306-1318.e5. doi: 10.1016/j.neuron.2017.08.038.


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.

Keywords: NMDA; Parkinson’s disease; basal ganglia; cortex; globus pallidus; glutamate; plasticity; subthalamic nucleus; synapse.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Cerebral Cortex / physiology*
  • Corpus Striatum / physiology*
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / physiology*
  • Gene Knockdown Techniques
  • Globus Pallidus / physiology*
  • Locomotion / drug effects
  • Locomotion / physiology
  • Long-Term Potentiation / physiology
  • Male
  • Mice
  • Mice, Transgenic
  • Neural Inhibition / physiology
  • Neural Pathways / physiology
  • Oxidopamine
  • Parkinson Disease / physiopathology
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Subthalamic Nucleus / physiology*
  • Synaptic Transmission / physiology


  • Receptors, N-Methyl-D-Aspartate
  • Oxidopamine