Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models

Neuron. 2016 Dec 21;92(6):1220-1237. doi: 10.1016/j.neuron.2016.10.064. Epub 2016 Dec 1.


Huntington's disease (HD) symptoms are driven to a large extent by dysfunction of the basal ganglia circuitry. HD patients exhibit reduced striatal phoshodiesterase 10 (PDE10) levels. Using HD mouse models that exhibit reduced PDE10, we demonstrate the benefit of pharmacologic PDE10 inhibition to acutely correct basal ganglia circuitry deficits. PDE10 inhibition restored corticostriatal input and boosted cortically driven indirect pathway activity. Cyclic nucleotide signaling is impaired in HD models, and PDE10 loss may represent a homeostatic adaptation to maintain signaling. Elevation of both cAMP and cGMP by PDE10 inhibition was required for rescue. Phosphoproteomic profiling of striatum in response to PDE10 inhibition highlighted plausible neural substrates responsible for the improvement. Early chronic PDE10 inhibition in Q175 mice showed improvements beyond those seen with acute administration after symptom onset, including partial reversal of striatal deregulated transcripts and the prevention of the emergence of HD neurophysiological deficits. VIDEO ABSTRACT.

Keywords: MP-10; PDE10A; PF-02545920; Q175; R6/2; cAMP; cGMP; corticostriatal; cyclic nucleotide; subthalamic nucleus.

Publication types

  • Video-Audio Media

MeSH terms

  • Animals
  • Basal Ganglia / diagnostic imaging
  • Basal Ganglia / drug effects
  • Basal Ganglia / metabolism
  • Basal Ganglia / physiopathology
  • Cerebral Cortex / diagnostic imaging
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / physiopathology
  • Cyclic AMP / metabolism
  • Cyclic GMP / metabolism
  • Disease Models, Animal
  • Huntington Disease / metabolism
  • Huntington Disease / physiopathology*
  • Mice
  • Neostriatum / diagnostic imaging
  • Neostriatum / drug effects*
  • Neostriatum / metabolism
  • Neostriatum / physiopathology
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphoric Diester Hydrolases
  • Positron-Emission Tomography
  • Pyrazoles / pharmacology*
  • Quinolines / pharmacology*
  • Subthalamic Nucleus / diagnostic imaging
  • Subthalamic Nucleus / drug effects
  • Subthalamic Nucleus / metabolism
  • Subthalamic Nucleus / physiopathology
  • Tritium


  • 2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline
  • Phosphodiesterase Inhibitors
  • Pyrazoles
  • Quinolines
  • Tritium
  • Cyclic AMP
  • Pde10a protein, mouse
  • Phosphoric Diester Hydrolases
  • Cyclic GMP